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Miao, Miao, Wu Depei, Aining Sun, Ying Wang, Lingzhi Yan e Qian Wu. "The Efficacy and Safety of Recombinant Human Thrombopoietin in Patients with Hematological Malgnancies After Allogeneic Hematopoietic Stem Cell Transplantation". Blood 118, n.º 21 (18 de novembro de 2011): 4565. http://dx.doi.org/10.1182/blood.v118.21.4565.4565.
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Abstract Abstract 4565 OBJECTIVE: To evaluate the efficacy and sefety of recombinant human thrombopoietin(rhTPO) prior to engraftment in adults with hematological malignancie who received allogeneic haematopoietil stem cell transplantation(Allo-HSCT). METHODS: This sutdy was a randomized, controlled clinical trial,38 patients were hematological malignancie, inclulding acute and chrinic myeloid leukemia, acute lymphoblastic leukemia, lymphoma.They received Allo-HSCT and were randomly divided into groups(group A 19 cases, group B 19 cases).The group A was no-rhTPO as control, the group B were received rhTPO 15000U/d from +1 day, and continued until the untransfused platelet count was >70×109/L for two consecutived days. Patients received platelete transfusion when they developed severe thrombocytopenia<20×109/L. Efficacy and sefety of rhTPO on the outcome of Allo-HSCT were evaluated. RESULTS: In both group A and B, platelet decrease after Allo-HSCT had no sognificant difference. The platelet engraftment duration of group A and B was 15.68±1.36(range 11–31) days and 13.47±0.72(range 9–21) days, respectively. The amount of platelet transfusion of group A and B was 4±0.55(range 20–130) units and 2.89±0.36(range 0–50) units, respectively. The effects of rhTPO on neutrophil engraftment, hepatic function, renal function, alloergic reations and acute GVHD were not found. CONCLUSION: The platelet engraftment duration of group B was shorter than that of group A(t=27.2, p<0.001), the amount of need platelet transfusion was significently less than those in the group A.There was a statistically significant difference in platelet engraftment and platelet transfusion needed(t=2.523, p<0.05). Administration of rhTPO prior to platelet engraftment after Allo-HSCT seem to be efficacy and safe. Disclosures: No relevant conflicts of interest to declare.
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Lydyard, Peter M., Andrew P. Jewell, Christoph Jamin e Pierre Y. Youinou. "CD5 B cells and B-cell malignancies". Current Opinion in Hematology 6, n.º 1 (janeiro de 1999): 30. http://dx.doi.org/10.1097/00062752-199901000-00006.
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Zweidler-McKay, Patrick A., Yiping He, Lanwei Xu, Carlos G. Rodriguez, Fredrick G. Karnell, Andrea C. Carpenter, Jon C. Aster, David Allman e Warren S. Pear. "Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies". Blood 106, n.º 12 (1 de dezembro de 2005): 3898–906. http://dx.doi.org/10.1182/blood-2005-01-0355.
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Although Notch receptor expression on malignant B cells is widespread, the effect of Notch signaling in these cells is poorly understood. To investigate Notch signaling in B-cell malignancy, we assayed the effect of Notch activation in multiple murine and human B-cell tumors, representing both immature and mature subtypes. Expression of constitutively active, truncated forms of the 4 mammalian Notch receptors (ICN1-4) inhibited growth and induced apoptosis in both murine and human B-cell lines but not T-cell lines. Similar results were obtained in human precursor B-cell acute lymphoblastic leukemia lines when Notch activation was achieved by coculture with fibroblasts expressing the Notch ligands Jagged1 or Jagged2. All 4 truncated Notch receptors, as well as the Jagged ligands, induced Hes1 transcription. Retroviral expression of Hairy/Enhancer of Split-1 (Hes1) recapitulated the Notch effects, suggesting that Hes1 is an important mediator of Notch-induced growth arrest and apoptosis in B cells. Among the B-cell malignancies that were susceptible to Notch-mediated growth inhibition/apoptosis were mature B-cell and therapy-resistant B-cell malignancies, including Hodgkin, myeloma, and mixed-lineage leukemia (MLL)–translocated cell lines. These results suggest that therapies capable of activating Notch/Hes1 signaling may have therapeutic potential in a wide range of human B-cell malignancies.
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Brudno, Jennifer N., Robert P. T. Somerville, Victoria Shi, Jeremy J. Rose, David C. Halverson, Daniel H. Fowler, Juan C. Gea-Banacloche et al. "Allogeneic T Cells That Express an Anti-CD19 Chimeric Antigen Receptor Induce Remissions of B-Cell Malignancies That Progress After Allogeneic Hematopoietic Stem-Cell Transplantation Without Causing Graft-Versus-Host Disease". Journal of Clinical Oncology 34, n.º 10 (1 de abril de 2016): 1112–21. http://dx.doi.org/10.1200/jco.2015.64.5929.
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Purpose Progressive malignancy is the leading cause of death after allogeneic hematopoietic stem-cell transplantation (alloHSCT). After alloHSCT, B-cell malignancies often are treated with unmanipulated donor lymphocyte infusions (DLIs) from the transplant donor. DLIs frequently are not effective at eradicating malignancy and often cause graft-versus-host disease, a potentially lethal immune response against normal recipient tissues. Methods We conducted a clinical trial of allogeneic T cells genetically engineered to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. Patients with B-cell malignancies that had progressed after alloHSCT received a single infusion of CAR T cells. No chemotherapy or other therapies were administered. The T cells were obtained from each recipient’s alloHSCT donor. Results Eight of 20 treated patients obtained remission, which included six complete remissions (CRs) and two partial remissions. The response rate was highest for acute lymphoblastic leukemia, with four of five patients obtaining minimal residual disease–negative CR. Responses also occurred in chronic lymphocytic leukemia and lymphoma. The longest ongoing CR was more than 30 months in a patient with chronic lymphocytic leukemia. New-onset acute graft-versus-host disease after CAR T-cell infusion developed in none of the patients. Toxicities included fever, tachycardia, and hypotension. Peak blood CAR T-cell levels were higher in patients who obtained remissions than in those who did not. Programmed cell death protein-1 expression was significantly elevated on CAR T cells after infusion. Presence of blood B cells before CAR T-cell infusion was associated with higher postinfusion CAR T-cell levels. Conclusion Allogeneic anti-CD19 CAR T cells can effectively treat B-cell malignancies that progress after alloHSCT. The findings point toward a future when antigen-specific T-cell therapies will play a central role in alloHSCT.
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Ren, Anqi, Xiqin Tong, Na Xu, Tongcun Zhang, Fuling Zhou e Haichuan Zhu. "CAR T-Cell Immunotherapy Treating T-ALL: Challenges and Opportunities". Vaccines 11, n.º 1 (12 de janeiro de 2023): 165. http://dx.doi.org/10.3390/vaccines11010165.
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T-cell acute lymphoblastic leukemia (T-ALL), a form of T-cell malignancy, is a typically aggressive hematological malignancy with high rates of disease relapse and a poor prognosis. Current guidelines do not recommend any specific treatments for these patients, and only allogeneic stem cell transplant, which is associated with potential risks and toxicities, is a curative therapy. Recent clinical trials showed that immunotherapies, including monoclonal antibodies, checkpoint inhibitors, and CAR T therapies, are successful in treating hematologic malignancies. CAR T cells, which specifically target the B-cell surface antigen CD19, have demonstrated remarkable efficacy in the treatment of B-cell acute leukemia, and some progress has been made in the treatment of other hematologic malignancies. However, the development of CAR T-cell immunotherapy targeting T-cell malignancies appears more challenging due to the potential risks of fratricide, T-cell aplasia, immunosuppression, and product contamination. In this review, we discuss the current status of and challenges related to CAR T-cell immunotherapy for T-ALL and review potential strategies to overcome these limitations.
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Hudecek, Michael, Thomas M. Schmitt, Sivasubramanian Baskar, Maria Teresa Lupo-Stanghellini, Tetsuya Nishida, Tori N. Yamamoto, Marie Bleakley et al. "The B-cell tumor–associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor". Blood 116, n.º 22 (25 de novembro de 2010): 4532–41. http://dx.doi.org/10.1182/blood-2010-05-283309.
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Monoclonal antibodies and T cells modified to express chimeric antigen receptors specific for B-cell lineage surface molecules such as CD20 exert antitumor activity in B-cell malignancies, but deplete normal B cells. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) was identified as a highly expressed gene in B-cell chronic lymphocytic leukemia (B-CLL), but not normal B cells, suggesting it may serve as a tumor-specific target for therapy. We analyzed ROR1-expression in normal nonhematopoietic and hematopoietic cells including B-cell precursors, and in hematopoietic malignancies. ROR1 has characteristics of an oncofetal gene and is expressed in undifferentiated embryonic stem cells, B-CLL and mantle cell lymphoma, but not in major adult tissues apart from low levels in adipose tissue and at an early stage of B-cell development. We constructed a ROR1-specific chimeric antigen receptor that when expressed in T cells from healthy donors or CLL patients conferred specific recognition of primary B-CLL and mantle cell lymphoma, including rare drug effluxing chemotherapy resistant tumor cells that have been implicated in maintaining the malignancy, but not mature normal B cells. T-cell therapies targeting ROR1 may be effective in B-CLL and other ROR1-positive tumors. However, the expression of ROR1 on some normal tissues suggests the potential for toxi-city to subsets of normal cells.
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Chattaraj, Asmi, Mohammad Ebad Ur Rehman, Israr Khan, Diana Franco, Atif Ibrahim, Razwana Khanam, Nayha Tahir et al. "Safety and efficacy of allogeneic CAR-T cells in B-cell malignancies: A systematic review and meta-analysis." Journal of Clinical Oncology 40, n.º 16_suppl (1 de junho de 2022): e19530-e19530. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e19530.
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e19530 Background: Immunotherapy with chimeric antigen receptor T (CAR-T) cells has proven effective in recent trials for patients with B cell malignancies, who relapsed after stem cell transplantation. Genetically modified allogeneic CAR T-cells used in advanced B cell malignancy engage with multiple target allo-antigens along with CD19 and/or CD20, leading to elimination of malignant B cells resulting in a potent graft versus malignancy effect with avoidance of tumor escape. Some concerns regarding their use exist like life-threatening graft-versus-host disease (GVHD) and rapid clearance by the host immune system. This study summarises the efficacy and safety of allogeneic CAR-T therapy in B cell malignancies. Methods: A systematic literature search was conducted on PubMed, Embase, Cochrane and Clinicaltrials.gov from inception to Jan 26, 2022, using MeSH terms and keywords for B cell malignancies and CAR-T therapy. We also screened the data presented in various conferences and handpicked references from previous systematic reviews. Outcomes of interest were complete remission (CR), 1-year overall survival (OS), GVHD, cytokine release syndrome (CRS), and immune effector cell associated neurotoxicity (ICANS). Proportional outcomes were pooled using a random effects model (Freeman-Tukey double arcsine transformation) in OpenMetaAnalyst software. Results: The initial search retrieved 1247 articles. After excluding reviews, duplicates and non-relevant articles, we included data from 9 clinical trials (n = 146 patients). The most common malignancy was acute lymphoblastic leukemia (125 patients, 86%). The median age of patients ranged from 19 to 49 years. All patients received CD19 targeting therapy and the cell dose administered ranged from 0.4×10^6 to 5×10^8 cells/kg. CR was reported in 93 of 146 patients, with a pooled rate of 63% (95% CI 47.4 - 78.6%; I2 78.5%). The pooled 1-year OS was 57.3% (95% CI 30.8 - 82%; I2 79.2%). The pooled proportion of GVHD was 9.4% (95% CI 3.1- 15.6%; I2 47.6%). The pooled CRS and ICANS rates were 59.3% (95% CI 30.5 - 88.1%; I2 95.2%) and 15.4% (95% CI 4.6 - 26.3%; I2 72.7%), respectively. Conclusions: Allogeneic CAR-T therapy has demonstrated acceptable efficacy and safety in B cell malignancies, with CR being reported in about 60% of patients and GVHD in < 10% of patients. Although allogeneic CAR-T cells are showing promise, several trials are ongoing and we need longer follow up.[Table: see text]
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Tonino, Sanne H., Marinus H. J. Van Oers, Rene A. Van Lier e Marie Jose Kersten. "CMV-Associated Expansion of CD8+CD45RA+CD27− T-Cells in Patients with B-Cell Malignancies." Blood 110, n.º 11 (16 de novembro de 2007): 3592. http://dx.doi.org/10.1182/blood.v110.11.3592.3592.
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Abstract In patients with various malignancies of B-cell origin, changes in the T-cell compartment have been observed. In B-cell chronic lymphocytic leukemia (CLL), we have previously described an expansion of T-cells, largely due to an increase in T-cells exhibiting the CD45RA+CD27- effector phenotype. This was found only in cytomegalovirus (CMV) seropositive patients, suggesting that CMV-antigen drives this expansion. Indeed a considerable fraction of these T-cells were shown to be CMV-specific. At present it is unknown whether this alteration of the T-cell compartment is specific for CLL or rather any B-cell malignancy could induce similar changes. We performed an immunophenotypic analysis of the T-cell compartment in the peripheral blood of 56 patients with a B-cell malignancy (CLL, n=16; indolent lymphoma, n=20; aggressive lymphoma, n=10; multiple myeloma, n=10) and 12 healthy controls. Subjects of the different disease categories and controls were age-matched. We assessed the total CD3 compartment, naïve (CD27+CD45RA+), memory (CD27+CD45RA−) and memory effector (CD27−CD45RA+) CD8+ T cells. Latent CMV infection was assessed both by CMV-IgG titers (ELISA) and CMV viral load (PCR). The absolute number of T-cells was significantly increased (2.5 – 3 fold) in CLL, but not in the other B-cell malignancies. However, in all disease categories the CD4/CD8 ratio was decreased when compared to healthy controls. This was due to a slight decrease in CD4+ T-cells and an increase in CD8+ T-cells. Irrespective of the nature of the malignancy, the expansion of CD8+ T-cells resulted from a significant increase in CD45RA+CD27− effector T-cells. In agreement with our previous observation, CD8+ T-cell changes were only found in CMV-seropositive patients. Based on our earlier studies we expect these T-cells to be CMV-specific. No correlation between CMV-specific antibody titers and effector T-cell numbers was found. We conclude that the, possibly CMV-specific, effector T-cell compartment is expanded in all B-cell maligancies, although these changes seem to be more pronounced in CLL. The expansion of the total T cell compartment is restricted to CLL. The skewing of the T-cell compartment in CMV-seropositive patients could be the result of increased pressure of latent CMV-infection on the cellular immune system due to failure of other aspects of host defence, brought about by the malignancy.
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Incrocci, Ryan, Molly McCormack e Michelle Swanson-Mungerson. "Epstein–Barr virus LMP2A increases IL-10 production in mitogen-stimulated primary B-cells and B-cell lymphomas". Journal of General Virology 94, n.º 5 (1 de maio de 2013): 1127–33. http://dx.doi.org/10.1099/vir.0.049221-0.
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Epstein–Barr virus (EBV) latently infected B-cells are the precursors of EBV-associated malignancies. EBV-infection induces the production of pro-survival and anti-inflammatory cytokines that may be important in the transition between latency and malignancy. One EBV protein, LMP2A, can be detected in both latently infected resting B-cells and in EBV-associated malignancies. Therefore, we tested the ability of LMP2A to influence cytokine production using both LMP2A-Tg primary B-cells and LMP2A-expressing B-cell lines. Our data demonstrate that LMP2A does not globally alter B-cell-produced cytokine levels, but specifically targets IL-10. Additional studies using ELISA and real-time-RT-PCR confirm that LMP2A utilizes PI3-kinase to increase IL-10 levels. Finally, the data demonstrate that LMP2A-expressing B-cell lines are more dependent on IL-10 for survival in comparison to LMP2A-negative B-cell lines. These data identify a novel function of LMP2A in the alteration of a cytokine that is important for both tumour survival and anti-tumour responses.
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Prakash, Ajay, e Alhossain A. Khalafallah. "Concurrent Hairy Cell Leukemia and Metastatic Merkel Cell Carcinoma". Case Reports in Oncological Medicine 2018 (14 de novembro de 2018): 1–6. http://dx.doi.org/10.1155/2018/1736854.
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Hairy cell leukemia (HCL) and Merkel cell carcinoma (MCC) are two rare malignancies with distinct cells of origin. HCL is a lymphoid malignancy of mature B cells, and MCC derives from neuroendocrine cell origin. HCL has a favorable prognosis with most patients achieving long-term remission and potential cure. In contrast, MCC is an aggressive malignancy affecting the skin and can metastasize quickly with a dismal prognosis. Immunocompromised patients, such as those with AIDS, posttransplant, and the elderly, have higher incidences than the general population, suggesting a possible immune mechanism. We report a case where a patient presented with HCL and metastatic MCC synchronously. This is the first reported case of these two rare malignancies occurring concurrently at initial presentation and may represent a role of immunosuppression in the pathogenesis of MCC.
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Maio, M., A. Pinto, A. Carbone, V. Zagonel, A. Gloghini, G. Marotta, D. Cirillo, A. Colombatti, F. Ferrara e L. Del Vecchio. "Differential expression of CD54/intercellular adhesion molecule-1 in myeloid leukemias and in lymphoproliferative disorders". Blood 76, n.º 4 (15 de agosto de 1990): 783–90. http://dx.doi.org/10.1182/blood.v76.4.783.783.
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Abstract Indirect immunofluorescence staining with monoclonal antibody (MoAb) CL203.4 of malignant cells from 269 patients with hematologic malignancies showed a heterogeneous expression of CD54/intercellular adhesion molecule-1 (ICAM-1). This marker was expressed by malignant cells of 57 out of 118 patients with myeloid malignancies and 69 out of 135 with B-lymphoid malignancies. On the other hand, CD54 was not detected on malignant cells of 16 patients with T-lymphoid malignancies. In myeloid malignancies, CD54 is preferentially expressed by “stem cell-derived” malignancies, being detectable on blast cells from almost all patients affected by chronic myelogenous leukemia in blast phase or myelodysplastic syndromes and by only 34% of patients with de novo acute myeloid leukemia (AML). The expression of CD54 did not correlate with any specific myeloid FAB subtype, although three cases of highly undifferentiated AML (FAB MO) displayed maximal levels of the antigen. The expression of CD54 in AML was significantly associated with that of CD34 and HLA-DR antigens. In B-lymphoid malignancies, CD54 expression appears to correlate with the differentiation stage of malignant cells, since B-origin acute lymphoblastic leukemias and conventional B-chronic lymphocytic leukemias (B-CLL; ie, “dim SIg” CLL) expressed lower levels of CD54 than more mature lymphoproliferative disorders (“bright SIg” CLL, prolymphocytic leukemias, and lymphoplasmacytic tumors). “High-grade” B- cell non-Hodgkin‧s lymphomas (B-NHL) express in general a higher level of CD54 than “low-grade” ones. This finding in conjunction with the expression of CD54 in all 17 patients with “bright SIg” CLL investigated (characterized by marked organomegaly and poor prognosis) suggest that the differential expression of CD54 in lymphoproliferative disorders may also relate to their degree of malignancy.
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Maio, M., A. Pinto, A. Carbone, V. Zagonel, A. Gloghini, G. Marotta, D. Cirillo, A. Colombatti, F. Ferrara e L. Del Vecchio. "Differential expression of CD54/intercellular adhesion molecule-1 in myeloid leukemias and in lymphoproliferative disorders". Blood 76, n.º 4 (15 de agosto de 1990): 783–90. http://dx.doi.org/10.1182/blood.v76.4.783.bloodjournal764783.
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Indirect immunofluorescence staining with monoclonal antibody (MoAb) CL203.4 of malignant cells from 269 patients with hematologic malignancies showed a heterogeneous expression of CD54/intercellular adhesion molecule-1 (ICAM-1). This marker was expressed by malignant cells of 57 out of 118 patients with myeloid malignancies and 69 out of 135 with B-lymphoid malignancies. On the other hand, CD54 was not detected on malignant cells of 16 patients with T-lymphoid malignancies. In myeloid malignancies, CD54 is preferentially expressed by “stem cell-derived” malignancies, being detectable on blast cells from almost all patients affected by chronic myelogenous leukemia in blast phase or myelodysplastic syndromes and by only 34% of patients with de novo acute myeloid leukemia (AML). The expression of CD54 did not correlate with any specific myeloid FAB subtype, although three cases of highly undifferentiated AML (FAB MO) displayed maximal levels of the antigen. The expression of CD54 in AML was significantly associated with that of CD34 and HLA-DR antigens. In B-lymphoid malignancies, CD54 expression appears to correlate with the differentiation stage of malignant cells, since B-origin acute lymphoblastic leukemias and conventional B-chronic lymphocytic leukemias (B-CLL; ie, “dim SIg” CLL) expressed lower levels of CD54 than more mature lymphoproliferative disorders (“bright SIg” CLL, prolymphocytic leukemias, and lymphoplasmacytic tumors). “High-grade” B- cell non-Hodgkin‧s lymphomas (B-NHL) express in general a higher level of CD54 than “low-grade” ones. This finding in conjunction with the expression of CD54 in all 17 patients with “bright SIg” CLL investigated (characterized by marked organomegaly and poor prognosis) suggest that the differential expression of CD54 in lymphoproliferative disorders may also relate to their degree of malignancy.
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Swanson-Mungerson, Michelle, Ryan Incrocci, Molly McCormack e Caroline Leof. "Effects of Epstein-Barr Virus Latent Membrane Protein 2A (LMP2A) on cytokine production in primary and transformed B cells (105.40)". Journal of Immunology 188, n.º 1_Supplement (1 de maio de 2012): 105.40. http://dx.doi.org/10.4049/jimmunol.188.supp.105.40.
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Abstract Epstein-Barr Virus (EBV) latently-infected B cells are precursors of EBV-associated malignancies. However, the transition from a latently-infected cell to a malignant tumor cell is poorly understood. Studies show that EBV modulates pro-survival and anti-inflammatory cytokine levels in EBV-transformed cell lines. However, gene expression in these cell lines may not reflect gene expression found in latent B cells and lymphomas. One EBV protein, LMP2A, is consistently detected in both latently-infected resting B cells, as well as in EBV-associated malignancies. Therefore, we hypothesized that LMP2A may modulate cytokines that aid in the transition between latency and malignancy. Cytokine array data analyzing B cells from LMP2A-transgenic mice and B cell lymphomas expressing LMP2A indicate that LMP2A does not globally alter B cell-produced cytokine levels, but rather targets a limited number of cytokines. Additional studies using ELISA and Real-time RT-PCR confirm that LMP2A increases IL-10 levels and flow cytometry reveals that LMP2A increases the amount of IL-10 produced per B cell. Inhibitors of the LMP2A signaling pathway are being tested to determine the signaling requirements for LMP2A-mediated increases in IL-10. These data identify a novel function of LMP2A in the alteration of a cytokine that is important for both tumor survival and anti-tumor responses.
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Kochenderfer, James N., Mark E. Dudley, Robert O. Carpenter, Sadik H. Kassim, Jeremy J. Rose, William Telford, Frances T. Hakim et al. "Donor-Derived Anti-CD19 Chimeric-Antigen-Receptor-Expressing T Cells Cause Regression Of Malignancy Persisting After Allogeneic Hematopoietic Stem Cell Transplantation". Blood 122, n.º 21 (15 de novembro de 2013): 151. http://dx.doi.org/10.1182/blood.v122.21.151.151.
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Abstract Progressive malignancy is a leading cause of death in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). To improve treatment of B-cell malignancies that persist despite alloHSCT, we conducted a clinical trial of allogeneic T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. Ten patients were treated on this trial. Four patients were recipients of human-leukocyte-antigen (HLA)-matched unrelated donor (URD) transplants and 6 patients were recipients of HLA-matched sibling transplants. T cells for genetic modification were obtained from each patient’s healthy alloHSCT donor. Patients received a single infusion of anti-CD19-CAR T cells. Cell doses ranged from 1x106 to 10x106 T cells/kg. A mean of 58% of the infused cells expressed the CAR. Patients did not receive chemotherapy or other anti-malignancy therapy with the CAR-T-cell infusions, so the responses observed in these patients are not confounded by the effects of chemotherapy. In contrast to other reports of successful treatment of B-cell malignancies with anti-CD19-CAR T cells, the patients on this study were not lymphocyte-depleted at the time of the CAR-T-cell infusions. Two patients with chronic lymphocytic leukemia (CLL) refractory to standard unmanipulated allogeneic donor lymphocyte infusions (DLIs) had regressions of large malignant lymph node masses after infusion of allogeneic anti-CD19-CAR T cells. One of these CLL patients obtained a complete remission that is ongoing 9 months after treatment with allogeneic anti-CD19-CAR T cells. This patient also had complete eradication of blood B cells within 9 days after her CAR-T-cell infusion. Another patient had tumor lysis syndrome requiring rasburicase treatment as his CLL dramatically regressed in lymph nodes, bone marrow, and blood within 2 weeks of his anti-CD19-CAR-T-cell infusion. A patient with mantle cell lymphoma obtained a partial remission that is ongoing 3 months after infusion of anti-CD19-CAR T cells. A fourth patient with diffuse large B-cell lymphoma has ongoing stable disease 11 months after infusion of anti-CD19-CAR T cells. The other 6 treated patients all had short periods of stable malignancy or progressive disease after their CAR-T-cell infusions. Specific eradication of blood B cells occurred after infusion of CAR T cells in 3 of 4 patients with measurable blood B cells pretreatment. None of the patients treated on this study developed GVHD after their anti-CD19-CAR-T-cell infusions, despite the fact that 6 of 10 treated patients had experienced GVHD at earlier time-points after their most recent alloHSCT. One patient, who had a history of cardiac dysfunction with prior acute illnesses, had temporary cardiac dysfunction after infusion of anti-CD19-CAR T cells. The most prominent toxicities experienced by patients were fever and hypotension; these peaked 5 to 12 days after CAR-T-cell infusions and resolved within 14 days after the T-cell infusions. Two patients had Grade 3 fever, and 2 patients had Grade 3 hypotension. No patients experienced Grade 4 toxicities that were attributable to the CAR-T-cell infusions. Elevated levels of serum interferon gamma were detected in 3 patients at the time that they were experiencing toxicities. We detected cells containing the anti-CD19-CAR gene in the blood of 8 of 10 patients. The peak blood levels of CAR T cells varied from undetec to 2.8% of peripheral blood mononuclear cells. The persistence of the CAR T cells in the blood of patients was limited to one month or less. When we assessed T cells from the blood of patients ex vivo, we found elevated levels of the T-cell inhibitory molecule programmed cell death protein-1 (PD-1) on CAR+ T cells compared to CAR-negative T cells. These results show for the first time that small numbers of donor-derived allogeneic anti-CD19-CAR T cells can cause regression of highly treatment-resistant B-cell malignancies after alloHSCT without causing GVHD. Malignancies that were resistant to standard DLIs regressed after anti-CD19-CAR-T-cell infusions. Future goals for improving this approach include enhancing the persistence of anti-CD19-CAR T cells and reducing toxicities. Infusion of allogeneic T cells genetically modified to recognize malignancy-associated antigens is a promising approach for treating residual malignancy after alloHSCT. Disclosures: No relevant conflicts of interest to declare.
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Dalla Pietà, Anna, Elisa Cappuzzello, Pierangela Palmerini, Annavera Ventura, Andrea Visentin, Giuseppe Astori, Katia Chieregato et al. "Innovative therapeutic strategy for B-cell malignancies that combines obinutuzumab and cytokine-induced killer cells". Journal for ImmunoTherapy of Cancer 9, n.º 7 (julho de 2021): e002475. http://dx.doi.org/10.1136/jitc-2021-002475.
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BackgroundPatients affected by aggressive B-cell malignancies who are resistant to primary or salvage chemoimmunotherapy have an extremely poor prognosis and limited therapeutic options. Promising therapeutic success has been achieved with the infusion of CD19 chimeric antigen receptor-T cells, but several limits still restrain the administration to a limited proportion of patients. This unmet clinical need might be fulfilled by an adoptive immunotherapy approach that combines cytokine-induced killer (CIK) cells and monoclonal antibodies (mAb) to the CD20 antigen. Indeed, CIK cells are an effector population endowed with antitumor activity, which can be further improved and antigen-specifically redirected by clinical-grade mAb triggering antibody-dependent cell-mediated cytotoxicity.MethodsCIK cells were generated from peripheral blood of patients affected by different B-cell malignancies using a blinatumomab-based cell culture protocol. Effector cells were combined with the anti-CD20 mAb obinutuzumab and their therapeutic activity was assessed both in vitro and in vivo.ResultsCIK cells were successfully expanded in clinically relevant numbers, starting from small volumes of peripheral blood with extremely low CD3+ counts and high tumor burden. This relied on the addition of blinatumumab in culture, which leads to the simultaneous expansion of effector cells and the complete elimination of the neoplastic component. Moreover, CIK cells were highly cytotoxic in vitro against both B-cell tumor cell lines and autologous neoplastic targets, and had a significant therapeutic efficacy against a B-cell malignancy patient-derived xenograft on in vivo transfer.ConclusionsThe combination of an easily expandable CIK cell effector population with a mAb already in clinical use establishes a tumor antigen-specific redirection strategy that can be rapidly translated into clinical practice, providing an effective therapeutic alternative for B-cell malignancies without any need for genetic modifications. Additionally, the approach can be potentially applied to an extremely vast array of different tumors by simply substituting the targeting mAb.
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Li, Yangqiu, Lijian Yang, Shaohua Chen, Suxia Geng, Grzegorz Przybylski e Christian A. Schmidt. "Changes in Thymic Recent Output Function in Patients with B-Cell Lymphocytic Malignancy." Blood 108, n.º 11 (16 de novembro de 2006): 4464. http://dx.doi.org/10.1182/blood.v108.11.4464.4464.
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Abstract Since 1998 the use of signal joint T cell receptor excision circles (sjTRECs) to study changes in the frequency of recent thymic emigrants was reported, this study drew attention to the fact that the level of sjTRECs can be used to estimate the recent thymic output function. Therefore, sjTRECs was used as a new marker for analysis of thymic output function in different immunodeficiency diseases, immune reconstitution in patients after stem cell transplantation. Defects of cellular immunity, however, may also play a role in hematologic malignancies. Little is known about the feature of T-cell immune state in B-cell lymphocytic malignancy. In order to identify number of naïve T-cells in B-cell lymphocytic malignancy, sjTRECs-content was determined in the mononuclear cell fraction and the sjTRECs-number was related to the number of T-cells (according to the number of CD3-positive cells). Quantitative analysis of sjTRECs in DNA of peripheral blood T cells from 45 cases with B-cell lymphocytic malignancy (including 17 cases with ALL, 4 cases with CLL, 15 cases with B-NHL and 6 cases with MM) were preformed by real-time PCR and TaqMan analysis, and 14 normal individuals as controls. The results showed a dramatic reduction of sjTRECs values in patients. Some cases no sjTRECs copies could be detected in 40000 T cells. The mean value of sjTRECs was 0.39±0.75 copies/1000 PBMCs in ALL, 0.11±0.15 copies/1000 PBMCs in B-CLL, 0.67±1.39 copies/1000 PBMCs in B-NHL, 0.91±1.16 copies/1000 PBMCs in MM patients, as compared with 4.1±3.65 copies/1000 PBMCs in normal individuals, the sjTRECs level in all goups of B-cells lymphocytic malignancy were significant decrease (p=0.0001, p=0.048, p=0.002) except MM group (p=0.053). However, when comparison of the sjTRECs value in CD3+ compartments, it was not statistically different from the sjTRECs counts between patients with ALL (3.91±7.20 copies/1000 CD3+cells) and normal individuals (6.36±5.28 copies/1000 CD3+cells) (p=0.2139), suggesting that the reduction of sjTRECs level in patients wit ALL may due to lower numbers of T cells in peripheral blood. In conclusions, the results suggest that some thymic dysfunction in T cell generation was detected at least in most patient with B-cell lymphocytic malignancy. However, whether this is due to clonal expansion of T-cells to antigens, or reflects impairment of immune function associated to the malignancy, remains an open question. In a prospective study sjTRECs levels will be determined in different T- cell compartments including CD45RA+, CD4+ and CD8+ cells and so on.
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Link, BK, e GJ Weiner. "Production and characterization of a bispecific IgG capable of inducing T-cell-mediated lysis of malignant B cells". Blood 81, n.º 12 (15 de junho de 1993): 3343–49. http://dx.doi.org/10.1182/blood.v81.12.3343.bloodjournal81123343.
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Bispecific monoclonal antibodies (bsabs) recognizing both CD3 and a tumor antigen can redirect T-cell-mediated cytotoxicity toward cells bearing that antigen. Such bsabs have been shown to be more effective than monospecific monoclonal antibodies (MoAbs) at preventing tumor growth in animal models of B-cell malignancy. The current studies describe the production and preliminary evaluation of a bsab designed to induce the lysis of malignant human B cells by human T cells. The bsab was obtained from a hybrid-hybridoma cell line produced by fusing OKT3-secreting hybridoma cells with hybridoma cells that secrete 1D10. 1D10 is an MoAb that recognizes an antigen found on a majority of malignant human B cells that has not been detected to a significant degree on normal resting or activated lymphocytes. High performance liquid chromatography (HPLC) was used to separate bsab from monospecific antibodies that were also present in the hybrid-hybridoma antibody product. The bsab was then evaluated in vitro for its ability to induce lysis of malignant B cells by activated T cells. The bsab consistently induced extensive lysis in vitro of 1D10 (+) cells, including both cell lines and cells obtained from patients with a variety of B-cell malignancies. No such effect was seen with activated T cells alone or activated T cells with monospecific antibody. No increased lysis was seen with 1D10 (-) cell lines. The bsab also mediated lysis of malignant B cells by autologous T cells. We conclude bsab containing an OKT3 arm and a 1D10 arm can induce T-cell-mediated lysis in a manner that is both potent and specific. This supports further evaluation of this bsab as a potential immunotherapy of B-cell malignancy.
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Sud, Amit, Subhayan Chattopadhyay, Hauke Thomsen, Kristina Sundquist, Jan Sundquist, Richard S. Houlston e Kari Hemminki. "Analysis of 153 115 patients with hematological malignancies refines the spectrum of familial risk". Blood 134, n.º 12 (8 de agosto de 2019): 960–69. http://dx.doi.org/10.1182/blood.2019001362.
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Abstract Sud and colleagues interrogated the familial risk of hematological malignancy in association with over 150 000 patients. The majority of hematological malignancies showed increased familial relative risk, most prominently in association with B-cell malignancies.
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Green, Michael R., e Ash A. Alizadeh. "Common progenitor cells in mature B-cell malignancies". Current Opinion in Hematology 21, n.º 4 (julho de 2014): 333–40. http://dx.doi.org/10.1097/moh.0000000000000049.
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Yazdani, Yaghoub, Mousa Mohammadnia-Afrouzi, Mehdi Yousefi, Enayat Anvari, Ghasem Ghalamfarsa, Hadi Hasannia, Sanam Sadreddini e Farhad Jadidi-Niaragh. "Myeloid-derived suppressor cells in B cell malignancies". Tumor Biology 36, n.º 10 (2 de setembro de 2015): 7339–53. http://dx.doi.org/10.1007/s13277-015-4004-z.
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Cooper, Kathrine A., Jonathan Lattell, Beverly Gonzalez, Stephanie Kliethermes e Sucha Nand. "Prevalence of Multiple Primary Hematologic Malignancies Seen at a Tertiary Care Center". Blood 126, n.º 23 (3 de dezembro de 2015): 5017. http://dx.doi.org/10.1182/blood.v126.23.5017.5017.
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Abstract Background: There is a paucity of data regarding patients who develop multiple unrelated hematologic malignancies. This study aims to determine the prevalence of two or more hematologic malignancies in the same patient at Loyola University Medical Center (LUMC) over a period of 7 years and to explore associations with certain clinical risk factors. Methods: After obtaining IRB approval, the electronic medical record was queried for various hematologic malignancies according to ICD-9 codes from 2007-2014. Chemotherapy-associated and transformed malignancies were excluded. In addition, the following data were collected: age at first and second diagnoses, gender, ethnicity, HIV, EBV, CMV, hepatitis B or C, JAK2 mutation, or autoimmune disorders. Survival outcomes and presence of coexisting solid tumors were assessed. Results: Of 5902 patients diagnosed with any hematologic malignancy, 27 were found to have more than one. Two patients had three hematologic malignancies (Hodgkin lymphoma, cutaneous t-cell lymphoma, diffuse large B-cell lymphoma; chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), MALT lymphoma, diffuse large B-cell lymphoma). The most common first hematologic malignancy was CLL/SLL (10) followed by chronic myeloid leukemia (CML) (5) and Hodgkin lymphoma (4). The most common second primary hematologic malignancy was Hodgkin lymphoma (5), followed by multiple myeloma or plasmacytoma (4), acute myeloid leukemia (3) and CLL or monoclonal B-cell lymphocytosis (3). Thirty-seven of all malignancies were lymphoid, 16 myeloid and one Kaposi's sarcoma. Fifteen had both a myeloid and lymphoid malignancy; the remaining 12 patients had either two myeloid or two lymphoid malignancies. Seven cases were diagnosed synchronously and 20 metachronously. The median interval between the first and second diagnosis was 3 years (range: 0.19 - 6.26). The average age at diagnosis of the first and second disease was 62.4 and 67.2 years. Although not tested for statistical differences, the median survival after first and second diagnosis was 4.9 and 0.8 years, respectively. Seven patients also had at least one solid tumor malignancy; three had two different solid tumors. One patient had rheumatoid arthritis and hypothyroidism (SLL followed by Hodgkin lymphoma). Two patients had hypothyroidism, and four had type two diabetes. One patient had hepatitis B, and another had hepatitis B and C. Males were five times more likely to die after the first malignancy diagnosis compared to females, irrespective of the type of malignancy (p=0.04). No association was seen between survival and type of first malignancy or whether the second diagnosis was of lymphoid or myeloid lineage. Conclusion: These data show that in patients presenting with a hematologic malignancy, the risk of developing a second hematologic malignancy over a 7 year period was low at 0.005% (27 out of 5902). In about half (15 out of 27) the second hematologic malignancy belonged to a separate lineage and about a quarter (7/27) developed solid tumors. About one fourth of the patients (7/27) had an autoimmune disorder. Males in this cohort had a five-fold increased risk of death compared to females. The second hematologic malignancy was an ominous development and was associated with a median survival of 0.8 years. These observations should be confirmed in a prospective study. Disclosures No relevant conflicts of interest to declare.
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Kroeze, Emma, Laura Arias Padilla, Max Bakker, Judith M. Boer, Melanie M. Hagleitner, Birgit Burkhardt, Takeshi Mori et al. "Pediatric Precursor B-Cell Lymphoblastic Malignancies: From Extramedullary to Medullary Involvement". Cancers 14, n.º 16 (12 de agosto de 2022): 3895. http://dx.doi.org/10.3390/cancers14163895.
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B-cell lymphoblastic lymphoma (BCP-LBL) and B-cell acute lymphoblastic leukemia (BCP-ALL) are the malignant counterparts of immature B-cells. BCP-ALL is the most common hematological malignancy in childhood, while BCP-LBL accounts for only 1% of all hematological malignancies in children. Therefore, BCP-ALL has been well studied and treatment protocols have changed over the last decades, whereas treatment for BCP-LBL has stayed roughly the same. Clinical characteristics of 364 pediatric patients with precursor B-cell malignancies were studied, consisting of BCP-LBL (n = 210) and BCP-ALL (n = 154) patients. Our results indicate that based on the clinical presentation of disease, B-cell malignancies probably represent a spectrum ranging from complete isolated medullary disease to apparent complete extramedullary disease. Hepatosplenomegaly and peripheral blood involvement are the most important discriminators, as both seen in 80% and 95% of the BCP-ALL patients and in 2% of the BCP-LBL patients, respectively. In addition, we show that the overall survival rates in this cohort differ significantly between BCP-LBL and BCP-ALL patients aged 1–18 years (p = 0.0080), and that the outcome for infants (0–1 years) with BCP-LBL is significantly decreased compared to BCP-LBL patients of all other pediatric ages (p < 0.0001).
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Link, BK, e GJ Weiner. "Production and characterization of a bispecific IgG capable of inducing T-cell-mediated lysis of malignant B cells". Blood 81, n.º 12 (15 de junho de 1993): 3343–49. http://dx.doi.org/10.1182/blood.v81.12.3343.3343.
Texto completo da fonteResumo:
Abstract Bispecific monoclonal antibodies (bsabs) recognizing both CD3 and a tumor antigen can redirect T-cell-mediated cytotoxicity toward cells bearing that antigen. Such bsabs have been shown to be more effective than monospecific monoclonal antibodies (MoAbs) at preventing tumor growth in animal models of B-cell malignancy. The current studies describe the production and preliminary evaluation of a bsab designed to induce the lysis of malignant human B cells by human T cells. The bsab was obtained from a hybrid-hybridoma cell line produced by fusing OKT3-secreting hybridoma cells with hybridoma cells that secrete 1D10. 1D10 is an MoAb that recognizes an antigen found on a majority of malignant human B cells that has not been detected to a significant degree on normal resting or activated lymphocytes. High performance liquid chromatography (HPLC) was used to separate bsab from monospecific antibodies that were also present in the hybrid-hybridoma antibody product. The bsab was then evaluated in vitro for its ability to induce lysis of malignant B cells by activated T cells. The bsab consistently induced extensive lysis in vitro of 1D10 (+) cells, including both cell lines and cells obtained from patients with a variety of B-cell malignancies. No such effect was seen with activated T cells alone or activated T cells with monospecific antibody. No increased lysis was seen with 1D10 (-) cell lines. The bsab also mediated lysis of malignant B cells by autologous T cells. We conclude bsab containing an OKT3 arm and a 1D10 arm can induce T-cell-mediated lysis in a manner that is both potent and specific. This supports further evaluation of this bsab as a potential immunotherapy of B-cell malignancy.
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Jacobs, Lauren M., Peter H. Wiernik, Janice P. Dutcher e Pablo Muxi. "Long-Term Response and Possible Cure of Patients With B-Cell Malignancies With Dose-Escalated Rituximab". Journal of Investigative Medicine High Impact Case Reports 5, n.º 1 (janeiro de 2017): 232470961769130. http://dx.doi.org/10.1177/2324709617691307.
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Rituximab (R), a chimeric monoclonal antibody targeting CD20 antigen on B-cells, has become a standard of care in the treatment of B-cell malignancies, most often in conjunction with cytotoxic chemotherapy. Activity has been demonstrated in many subtypes of B-cell lymphoma, including diffuse large cell lymphoma, follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), lymphocyte-predominant Hodgkin lymphoma, and Waldenström macroglobulinemia (WM). Additionally, dose escalation of R as a single agent has demonstrated improved activity in previously treated/poor prognosis CLL. We present 4 cases of B-cell malignancy (2 CLL variants/MCL, 1 FL, 1 WM) who received dose-escalated R as a single agent and achieved complete response (3 patients) and stable disease/partial response (1 patient) of 6.5+ to 15+ years duration. They have been off treatment for 6.5+ to 15+ years. Toxicity was minimal, with initial infusion reactions similar to those observed with standard dose infusions. There were no serious treatment-related adverse events or infections. Dose escalated R as a single agent may possibly be curative for some patients with B-cell malignancies, unlike the standard empiric dose of 375 mg/m2, and deserves further study.
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Weng, Jinsheng, Flavio Egidio Baio, Kelsey E. Moriarty, Hiroki Torikai, Hua Wang, Zhiqiang Liu, Sourindra N. Maiti et al. "Targeting B-cell malignancies through human B-cell receptor specific CD4+T cells". OncoImmunology 5, n.º 11 (19 de setembro de 2016): e1232220. http://dx.doi.org/10.1080/2162402x.2016.1232220.
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Ghimire, Krishna B., e Binay K. Shah. "Second Primary Malignancy in Diffuse Large B Cell Lymphoma (DLBCL)". Blood 124, n.º 21 (6 de dezembro de 2014): 2606. http://dx.doi.org/10.1182/blood.v124.21.2606.2606.
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Introduction: Patients with non-Hodgkin lymphoma are at significantly increased risk of second primary malignancies (SPM). There are few studies on SPM in diffuse large B-cell lymphoma. We aim to evaluate the risk of SPM after diagnosis of primary DLBCL using Surveillance, Epidemiology and End Results (SEER) database. Methods: We used SEER 13 database to select adult patients with primary DLBCL diagnosed between 1992- 2009. We used SEER*Stat’s Multiple Primary - Standardized Incidence Ratios (MP-SIR) to calculate SPM in DLBCL. We analyzed SPM by age (≥20, 20-59 and ≥60 years), sex and latency. Second primary malignancy was defined as a metachronous malignancy developing six months or more after an index DLBCL. Results: A total of 28,368 adult DLBCL patients were selected for analysis. Among them, 54.4% were male, 44.1% were <60 years of age. The total number (n) of all site SPMs in DLBCL patients was 2,597, an Observed/ Expected (O/E) ratio of 1.22, P< 0.05, excess risk of 30.93. The risk of following SPMs was significantly higher in the patients with DLBCL: head & neck, anus & colorectal, lung, skin (melanoma), kidney, thyroid, Kaposi sarcoma and hematological malignancies. In young DLBCL patients (20-59 years) group, 12,509 patients developed 830 all site SPMs with O/E: 1.56, P value < 0.05, excess risk 37.01. SPMs which were significantly increased as compared to general population were: head & neck, anus & colorectal, lung, kidney, thyroid, Kaposi sarcoma and hematological malignancies. Similarly, 15,859 older (≥60 years) DLBCL patients developed 1,767 all site SPMs with O/E: 1.11, P< 0.05, excess risk 24.07. SPMs which were significantly increased in this age group as compared to general population were: head & neck, skin, colon, kidney, thyroid and hematologic malignancies. There was significantly higher risk of tumors of anus & colorectal, liver, kidney, thyroid, Kaposi sarcoma and hematologic malignancies within 5 years of latency. Malignancies of head & neck, anus &, colorectal, skin, breast, urinary bladder and hematologic malignancies were significantly higher after 5 years of latency. Conclusion: Patients with DLBCL were at significantly increased risk of developing SPMs as compared to general population. Survivors of DLBCL need to be closely followed with special attention to SPM. Disclosures No relevant conflicts of interest to declare.
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Sabbah, Shereen, Ya Jankey Jagne, Jianmin Zuo, Thushan de Silva, Mohammad M. Ahasan, Christian Brander, Sarah Rowland-Jones, Katie L. Flanagan e Andrew D. Hislop. "T-cell immunity to Kaposi sarcoma–associated herpesvirus: recognition of primary effusion lymphoma by LANA-specific CD4+ T cells". Blood 119, n.º 9 (1 de março de 2012): 2083–92. http://dx.doi.org/10.1182/blood-2011-07-366476.
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Abstract T-cell immunity is important for controlling Kaposi sarcoma–associated herpesvirus (KSHV) diseases such as the endothelial cell malignancy Kaposi sarcoma, or the B-cell malignancy, primary effusion lymphoma (PEL). However, little is known about KSHV-specific T-cell immunity in healthy donors and immune control of disease. Using PBMCs from healthy KSHV-infected donors, we found weak ex vivo responses to the KSHV latent antigens LANA, vFLIP, vCyclin, and Kaposin, with LANA most frequently recognized. CD4+ T-cell clones specific to LANA, a protein expressed in all KSHV-infected cells and malignancies, were established to determine whether they could recognize LANA-expressing cells. B-cell targets expressing or fed LANA protein were consistently recognized by the clones; however, most PEL cell lines were not. PELs express the KSHV protein vIRF3 that inhibits promoter function of the HLA class II transactivator, decreasing expression of genes controlled by this transactivator. Re-expressing the class II transactivator in the PELs increased expression of downstream targets such as HLA class II and restored recognition but not killing by the LANA-specific clones. We suggest that PELs are poorly controlled in vivo because of inefficient recognition and killing by T cells.
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Zhao, Zhigang, Lin Li, Meelad Dawlaty, Feng Pan, Zhe Li, Yuan Zhou, Hui Shi et al. "Combined Loss of Tet1 and Tet2 Promotes B-Cell, but Not Myeloid Malignancies in Mice". Blood 126, n.º 23 (3 de dezembro de 2015): 3650. http://dx.doi.org/10.1182/blood.v126.23.3650.3650.
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Abstract Objective: Tet1/2/3 are methylcytosine dioxygenases regulating cytosine methylation in the genome. Tet1 and Tet2 are abundantly expressed in HSC/HPCs and implicated in hematological malignancies. Tet2 -deletion in mice causes myeloid malignancies, while Tet1 -null mice are overtly normal early in life. Here, we investigated the overlapping and non-redundant functions of Tet1/Tet2 in HSC maintenance and hematological malignancies using Tet1/2 double knockout (DKO) mice. Methods: 1) Kinetic analysis of the hematologicalparameters on WT, Tet1-/-, Tet2-/- and DKO mice; 2) Analysis of HSC, myeloid and lymphoid progenitors and various maturation stages of B-cell populations; 3) Competitive bone marrow reconstitution assay; 4) RAN-Seq on LK cells and B220+ cells from young/undiseased and diseased DKO mice respectively; 5) Chemical labeling and affinity purification method coupled with high-throughput sequencing (hMe-Seal) to profile the genome-wide distribution of 5hmC, and methylated DNA immunoprecipitation coupled with high-throughput sequencing (MeDIP-seq) to profile 5mC in BM LK cells from young WT, Tet2-/- and DKO mice; 6) q-PCR analysis of the mRNA expression levels of Tet1 and Tet2 on BM CD19+ cells from B-ALL patients and compared to that of CD19+ B-cells from healthy controls. Results: We found that T et 1 and T et 2 are often concomitantly down-regulatedin patients with B-ALL. Therefore, it is important to investigate the effects of combined loss of Tet1 and Tet2 on the hematopoietic phenotype and development of hematological malignancies in vivo. The LSK and CMP/GMP/MEP cell populations are comparable in yound WT, Tet1-/- and DKO mice, while were significantly increasedin Tet2-/- mice. When a replating assay was performed using LSK cells, Tet2-/- LSK cell cultures had a significant higher colony formation in each round of replating, while Tet1-/- and DKO LSK cell cultures only exhibited a moderate increase in the number of colonies at P2, but not P3 and P4. Furthermore, young DKO mice had an increased percentage of CLP, BLP and Pro-/Pre-/Immature-B cell populations in their BM as compared to WT, Tet1-/- and Tet2-/- mice. Consistent to the B-lineage phenotypic analysis, DKO BM cells contained higher pre-B cell colony forming cells than the three genotypes of control mice. Interestingly, DKO mice exhibited a strikingly decreased incidence and delayed onset of myeloid malignancies compared to Tet2-/- mice and in contrast developed lethal B-cell malignancies, most closely resembling B-ALL. The loss of Tet2 or DKO leads to genome-wide alterations of both 5mC and 5hmC. Significant overlaps between the differential hydroxymethylated regions (DhMRs) or differential methylated regions (DMRs) of two genotypes of LK cells were observed. However, intriguingly, the overlaps between DhMRs and DMRs within each genotype of LK cells were minimal, indicating that DhMRs and DMRs might represent distinct loci with altered epigenetic modifications under these conditions. When the expression of a pool of 654 genes that are known to be involved in regulating hematopoietic cell development and/or promoting leukemogenesis were overlap with DhMRs and DMRs identified above, we observed significant numbers of these genes with altered either 5hmC or 5mC modifications which however did not alter their gene expression. Furthermore, RNA-Seq on B-ALL DKO B220+ cells showed alteration of a set of genes involved in B-cell development and B-cell lymphoma/leukemogenesis. Conclusion: Using Tet1/2 double knockout mice, we found that Tet1 is required for Tet2 -deletion mediated HSC dysregulation, myeloid skewing and myeloid malignancy, indicating distinct roles of the two enzymes. Tet1 loss modulates the Tet2 -deletion mediated disease phenotype, not only decreasing the incidence and delaying the onset of myeloid malignancies, but also promoting the pathogenesis of B-cell malignancies. Furthermore, our observations highlight the roles of distinct cytosine modifications, particularly 5hmC, could play in marking the specific genes and enabling cells to fate decision change upon stimulation signals. These findings provide a pathological framework for further elucidating the molecular mechanisms and critical cross talks between Tet1 and Tet2 in the pathogenesis of hematological malignancies. Disclosures No relevant conflicts of interest to declare.
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Chintapatla, Rangaswamy, Leticia Varella, Peter Wiernik, Valerie Rusciano e Janice P. Dutcher. "Association of Renal Cell Carcinoma and B-Cell Hematological Malignancy". Blood 120, n.º 21 (16 de novembro de 2012): 5086. http://dx.doi.org/10.1182/blood.v120.21.5086.5086.
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Abstract Abstract 5086 Purpose of the study: We observed an increased frequency of hematologic malignancy (HM) in patients and family members of patients with renal cell cancer (RCC) and sought to characterize the association further in terms of frequency and characteristics of HM, and the importance of such an association. Methods: We performed a chart review of our data base of approximately 700 RCC patients seen by us from 2004 to the present in an effort to determine the frequency of HM in patients and in the families of patients diagnosed with RCC. Results: Of the 700 charts reviewed, both HM and RCC occurred in 19 individuals. [11 males and 8 females]. HM diagnosis included acute myeloid leukemia in 1 patient, Hodgkin's lymphoma (HL) in 4 pts, non-Hodgkin lymphoma (NHL) in 7 pts, (3 small cell and 4 large B-cell lymphoma), chronic lymphocytic leukemia (CLL) in 2 pts and hairy cell leukemia (HCL), monoclonal gammopathy of undetermined significance (MGUS) myelodysplasia (MDS) in one patient each. A family history of HM was found in 71 relatives involving 56 families of patients with RCC. Of these, 48/71 cases of HM were in first degree relatives and 18/71 were in second degree relatives. The most common HMs were lymphoma and leukemia: 24 NHL, 9 HL, 6 lymphoma not further specified (NOS), 11 CLL, 1 acute myeloid leukemia, 5 acute leukemia NOS and 6 leukemia NOS. Other HM observed once were multiple myeloma, Waldenström's macroglobulinemia, chronic myeloid leukemia, myelofibrosis and polycythemia vera. In addition, 2 family members had blood cancers that were NOS. Thus, of 77 patients/family members with known HM diagnosis 94% were B-cell malignancies. Clear cell histology was the most common subtype of RCC, and all subtypes of RCC occurred in the study population with expected frequency. RCC and HM occurred in the same patient in this study more frequently at 2. 7% than would be expected from a SEER database. In that database the observed to expected (O/E) ratio of NHL and RCC was 1. 86 to 2. 07% [Kunthur et al. Am J Hematol 2006; 81:271–80]. Conclusions: Increased incidence of B-cell malignancy has been reported in individuals with RCC [Dutcher et al. Proc Am Fed Clin Res, Eastern Division, April 2011]. Wiernik et al. [Cancer J 2000] reported a similar increase was noted between adenocarcinoma of the breast and B cell malignancies in same individual and mouse mammary tumor virus was proposed a potential causative agent. There is a preponderance of B-cell malignancy in both the individuals and in the families of the patients with RCC noted in this study. The etiology of this association between RCC and HM is unclear and suggests a common etiopathogenesis for RCC and B-cell tumors, or a familial immunologic defect that facilitates both malignancies. We plan to further explore the relationship of HM to RCC. Disclosures: No relevant conflicts of interest to declare.
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Zhang, Jenny, Dereje D. Jima, Yuan Gao, Han Wu, Jun Zhu, Mark deLong, Peter E. Lipsky e Sandeep S. Dave. "Massively Parallel High Throughput Sequencing Identifies Novel Micrornas in Normal and Malignant B Cells." Blood 112, n.º 11 (16 de novembro de 2008): 3350. http://dx.doi.org/10.1182/blood.v112.11.3350.3350.
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Abstract Background: MicroRNAs (miRNAs) are small non coding RNAs that have been shown to play a regulatory role in a number of different settings including development, hematopoiesis and lineage-selection. The expression patterns of miRNAs in various cellular processes and in various normal and malignant tissues are an area of active exploration. Bioinformatic analyses of the genome suggest that there might be thousands of miRNAs encoded in the genome. However, thus far only about 600 unique miRNAs have been identified in humans. The role of microRNAs in B cell malignancies is poorly understood. Mature B cells comprise naive, germinal center, memory and plasma cells. These B cell stages comprise the majority of leukemias and lymphomas. We have previously demonstrated a role for microRNAs in the regulation of key transcription factors and oncogenes including PRDM1, LMO2 and MYBL1. We hypothesized that microRNAs play a role in the pathogenesis of lymphomas and have applied high throughput sequencing to understand the pattern and function of microRNA expression in normal B cells and their malignant counterparts. Methods: CD19+ mature B cells were obtained from normal patients undergoing tonsillectomy and sorted using flow cytometry into naive, germinal center, memory and plasma cells. We also obtained cells from tumor cell lines derived from mantle cell lymphoma (Mino, JVM2), Burkitt lymphoma (Ramos, BL41) and multiple myeloma (H929, U266), as well as patient tumor samples derived from Burkitt lymphoma and diffuse large B cell lymphomas. From these cells, we purified small RNAs (18-25 nucleotides) and ligated sequencing adapters to these small RNAs and subjected them to 15 cycles of PCR amplification. The constructs were then subjected to massively parallel high throughput sequencing (Illumina) in picoliter wells to identify millions of sequences per sample. Sequences thus identified were matched to the genome and microRNAs were identified based on their characteristic stem-loop secondary structure, thermodynamic stability, and evidence of processing with the microRNA-related enzymes drosha and dicer. Results: Using massively parallel high-throughput sequencing of small RNAs isolated from these B cell subsets, we analyzed a total of 62,293,147 sequences (> 1.6 billion bases). We found that 261 known microRNAs are expressed in normal and malignant B cells, a number that is three times higher than previously recognized. Our work also identified the expression of 86 novel miRNAs in normal and malignant B cells, many of which appear to target genes important in B cell differentiation including BCL6, NLK, EBF, as well as oncogenes including MYC, LMO2, and CCND1. We found no evidence of decreased expression of microRNAs in B cell malignancies, in contrast to the described down-regulation of microRNAs in tumors from other lineages. On the other hand, there were striking differences between the microRNA expression patterns in normal and malignant B cells, although B cell malignancies still frequently express miRNAs that are characteristic of their normal B cell counterpart. Each malignancy had a characteristic pattern of microRNA expression that was distinct from other malignancies and normal B cells. Conclusion: Through high throughput sequencing, we have discovered novel microRNAs that target important oncogenes including BCL6, MYC, LMO2, and CCND1, suggesting a role for microRNAs in B cell lymphomas.
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Miletic, Ana V., Amy N. Anzelon-Mills, David M. Mills, Sidne A. Omori, Irene M. Pedersen, Dong-Mi Shin, Jeffrey V. Ravetch, Silvia Bolland, Herbert C. Morse e Robert C. Rickert. "Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases". Journal of Experimental Medicine 207, n.º 11 (18 de outubro de 2010): 2407–20. http://dx.doi.org/10.1084/jem.20091962.
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The inositol phosphatases phosphatase and tensin homologue (PTEN) and Src homology 2 domain–containing inositol phosphatase (SHIP) negatively regulate phosphatidylinositol-3-kinase (PI3K)–mediated growth, survival, and proliferation of hematopoietic cells. Although deletion of PTEN in mouse T cells results in lethal T cell lymphomas, we find that animals lacking PTEN or SHIP in B cells show no evidence of malignancy. However, concomitant deletion of PTEN and SHIP (bPTEN/SHIP−/−) results in spontaneous and lethal mature B cell neoplasms consistent with marginal zone lymphoma or, less frequently, follicular or centroblastic lymphoma. bPTEN/SHIP−/− B cells exhibit enhanced survival and express more MCL1 and less Bim. These cells also express low amounts of p27kip1 and high amounts of cyclin D3 and thus appear poised to undergo proliferative expansion. Unlike normal B cells, bPTEN/SHIP−/− B cells proliferate to the prosurvival factor B cell activating factor (BAFF). Interestingly, although BAFF availability may promote lymphoma progression, we demonstrate that BAFF is not required for the expansion of transferred bPTEN/SHIP−/− B cells. This study reveals that PTEN and SHIP act cooperatively to suppress B cell lymphoma and provides the first direct evidence that SHIP is a tumor suppressor. As such, assessment of both PTEN and SHIP function are relevant to understanding the etiology of human B cell malignancies that exhibit augmented activation of the PI3K pathway.
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Chen, Zhengshan, e Markus Muschen. "Autoimmunity Checkpoints As Therapeutic Targets in B-Cell Malignancies". Blood 132, Supplement 1 (29 de novembro de 2018): 1587. http://dx.doi.org/10.1182/blood-2018-99-113674.
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Abstract Concept. Targeted therapy of cancer typically focuses on inhibitors (e.g. tyrosine kinase inhibitors) that suppress oncogenic signaling below a minimum threshold required for survival and proliferation of cancer cells. Acute lymphoblastic leukemia (ALL) and B cell lymphomas originate from various stages of development of B cells, which unlike other cell types are under intense selective pressure. The vast majority of newly generated B cells are autoreactive and die by negative selection at autoimmunity checkpoints (AIC). Owing to ubiquitous encounter of self-antigen, autoreactive B cells are eliminated by overwhelming signaling strength of their autoreactive B cell antigen receptor (BCR). A series of recent findings suggests that, despite malignant transformation, AIC are fully functional in B cell malignancies. We propose that targeted engagement of AIC represents a previously unrecognized therapeutic opportunity to overcome conventional mechanisms of drug-resistance in pre-B ALL and other B cell malignancies. Results: Oncogenic drivers in B- cell malignancies function as mimics of B-cell receptor (BCR) signaling. Oncogenic activation of BCR-signaling represents the functional equivalent of positive selection during normal lymphocyte development. Addiction to survival and proliferation signals (or the equivalent of positive selection) is a common feature in many types of cancer. However, B-cell malignancies are unique in that they are also subject to an active negative selection process. B-cells expressing autoreactive BCRs or antibodies can cause systemic autoimmunity. As a safeguard against autoimmune diseases, lymphocyte development evolved autoimmunity checkpoints (AIC) to eliminate autoreactive clones. Owing to negative selection of autoreactive B-cells through AIC activation, lymphoid cells fundamentally differ in their signaling requirements from other cell types. Recent studies from our group showed that despite malignant transformation, B-cell leukemia and lymphoma cells are fully sensitive to negative selection and AIC-activation resulting (Chen et al., Nature 2015; Shojaee et al., Nature Med 2016; Chan et al., Nature 2017; Xiao et al., Cell 2018). AIC-activation in various lymphoid malignancies is achievable by pharmacological hyperactivation of BCR-signaling above a maximum threshold (see Schematic below). Unlike other types of cancer, B-cell malignancies are uniquely susceptible to clonal deletion induced by hyperactive signaling from an autoreactive BCR. Hence, targeted AIC-activation can be leveraged for eradication of drug-resistant leukemia and lymphoma clones. Here, we propose a novel strategy to overcome drug-resistance in B-lymphoid malignancies based on targeted activation of autoimmunity checkpoints (AIC) for removal of autoreactive B-lymphocytes. We have recently discovered that targeted hyperactivation of SYK, PI3K and ERK in B cell malignancies represents the functional equivalent of an autoimmunity checkpoint (AIC) for elimination of autoreactive clones among normal B cells. B cell tumors are uniquely vulnerable to AIC activation, suggesting that targeted activation of this checkpoint represents a novel strategy to induce cell death in otherwise drug-resistant B cell malignancies. Conclusion: Normal B-cells are positively selected for BCR signaling of intermediate strength (moderate activation of SYK, PI3K and ERK). In the absence of a functional BCR, SYK, PI3K and ERK activity fall below a minimum threshold, resulting in death by neglect. Hyperactivation above maximum thresholds (e.g. autoreactive BCR) triggers negative selection and cell death via AIC-activation. Targeted therapy of cancer typically focuses on agents that suppress oncogenic signaling below a minimum threshold. Our results support a novel strategy to overcome drug-resistance in B-cell malignancies based on targeted activation of autoimmunity checkpoints (AIC) for removal of autoreactive cells. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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Lichtman, Eben I., e Gianpietro Dotti. "Chimeric antigen receptor T-cells for B-cell malignancies". Translational Research 187 (setembro de 2017): 59–82. http://dx.doi.org/10.1016/j.trsl.2017.06.011.
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Michels, Kathryn R., Alyssa Sheih, Susana A. Hernandez, Alissa H. Brandes, Don Parrilla, Blythe Irwin, Anai M. Perez et al. "Preclinical proof of concept for VivoVec, a lentiviral-based platform for in vivo CAR T-cell engineering". Journal for ImmunoTherapy of Cancer 11, n.º 3 (março de 2023): e006292. http://dx.doi.org/10.1136/jitc-2022-006292.
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BackgroundChimeric antigen receptor (CAR) T-cell therapies have demonstrated transformational outcomes in the treatment of B-cell malignancies, but their widespread use is hindered by technical and logistical challenges associated with ex vivo cell manufacturing. To overcome these challenges, we developed VivoVec, a lentiviral vector-based platform for in vivo engineering of T cells. UB-VV100, a VivoVec clinical candidate for the treatment of B-cell malignancies, displays an anti-CD3 single-chain variable fragment (scFv) on the surface and delivers a genetic payload that encodes a second-generation CD19-targeted CAR along with a rapamycin-activated cytokine receptor (RACR) system designed to overcome the need for lymphodepleting chemotherapy in supporting successful CAR T-cell expansion and persistence. In the presence of exogenous rapamycin, non-transduced immune cells are suppressed, while the RACR system in transduced cells converts rapamycin binding to an interleukin (IL)-2/IL-15 signal to promote proliferation.MethodsUB-VV100 was administered to peripheral blood mononuclear cells (PBMCs) from healthy donors and from patients with B-cell malignancy without additional stimulation. Cultures were assessed for CAR T-cell transduction and function. Biodistribution was evaluated in CD34-humanized mice and in canines. In vivo efficacy was evaluated against normal B cells in CD34-humanized mice and against systemic tumor xenografts in PBMC-humanized mice.ResultsIn vitro, administration of UB-VV100 resulted in dose-dependent and anti-CD3 scFv-dependent T-cell activation and CAR T-cell transduction. The resulting CAR T cells exhibited selective expansion in rapamycin and antigen-dependent activity against malignant B-cell targets. In humanized mouse and canine studies, UB-VV100 demonstrated a favorable biodistribution profile, with transduction events limited to the immune compartment after intranodal or intraperitoneal administration. Administration of UB-VV100 to humanized mice engrafted with B-cell tumors resulted in CAR T-cell transduction, expansion, and elimination of systemic malignancy.ConclusionsThese findings demonstrate that UB-VV100 generates functional CAR T cells in vivo, which could expand patient access to CAR T technology in both hematological and solid tumors without the need for ex vivo cell manufacturing.
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Zhang, Jenny, Dereje D. Jima, Cassandra Jacobs, Randy Fischer, Eva Gottwein, Grace Huang, Patricia L. Lugar et al. "Patterns of microRNA expression characterize stages of human B-cell differentiation". Blood 113, n.º 19 (7 de maio de 2009): 4586–94. http://dx.doi.org/10.1182/blood-2008-09-178186.
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Abstract Mature B-cell differentiation provides an important mechanism for the acquisition of adaptive immunity. Malignancies derived from mature B cells constitute the majority of leukemias and lymphomas. These malignancies often maintain the characteristics of the normal B cells that they are derived from, a feature that is frequently used in their diagnosis. The role of microRNAs in mature B cells is largely unknown. Through concomitant microRNA and mRNA profiling, we demonstrate a potential regulatory role for microRNAs at every stage of the mature B-cell differentiation process. In addition, we have experimentally identified a direct role for the microRNA regulation of key transcription factors in B-cell differentiation: LMO2 and PRDM1 (Blimp1). We also profiled the microRNA of B-cell tumors derived from diffuse large B-cell lymphoma, Burkitt lymphoma, and chronic lymphocytic leukemia. We found that, in contrast to many other malignancies, common B-cell malignancies do not down-regulate microRNA expression. Although these tumors could be distinguished from each other with use of microRNA expression, each tumor type maintained the expression of the lineage-specific microRNAs. Expression of these lineage-specific microRNAs could correctly predict the lineage of B-cell malignancies in more than 95% of the cases. Thus, our data demonstrate that microRNAs may be important in maintaining the mature B-cell phenotype in normal and malignant B cells.
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Yavuz, Selim A., Dan-Paul Hartmann, Said Baidas, Peter E. Lipsky e Metin Ozdemirli. "Demonstration of Biclonal Chronic Lymphocytic Leukemia with Mutated and Unmutated Clones and Concurrent but Clonally Unrelated Myeloma in the Same Patient by Single Cell Immunoglobulin Heavy and Light Chain Gene Analysis." Blood 104, n.º 11 (16 de novembro de 2004): 4772. http://dx.doi.org/10.1182/blood.v104.11.4772.4772.
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Abstract Patients with chronic lymphocytic leukemia (CLL) may develop other B cell malignancies in their clinical course including aggressive diffuse large B-cell lymphomas and rarely myelomas. In a large proportion of cases, the secondary B cell malignancies reflected the emergence of immunophenotypically and genetically different clones. An immature type plasma cell myeloma developed in a 73-year-old female patient in whom CLL was diagnosed four years previously. The CLL expressed CD5, CD19, CD23, CD38 and surface kappa light chain, but were negative for ZAP-70. Trisomy 12 was detected by FISH analysis. PCR analysis of the peripheral blood for immunoglobulin heavy chain genes demonstrated two sharp bands that were initially interpreted as biallelic heavy chain gene rearrangements. Myeloma cells were CD38 and CD138 positive, CD19 negative and expressed cytoplasmic kappa light chain, but not heavy chains. In order to investigate the clonal relationship between these B cell malignancies, a detailed analysis of VHDJH and VκJκ gene rearrangements in individually sorted CD5 and CD19 double-positive CLL cells and also in CD38-positive and CD19-negative myeloma cells by single cell PCR of genomic DNA and direct sequencing was carried out. This technique permitted identification and pairing of both the heavy and light chain immunoglobulin genes from the same individually sorted cell. A total of 17 individual CLL and 23 myeloma cells were successfully analyzed. Our analysis demonstrated (a) the presence of two discrete clones of CLL, one with usage of [VH1-2*04/D3-3*01/J3*02]-[Vκ2-28*01/J1*01] without VH and Vκ hypermutation and the other with usage of [VH1-2*04/D4-11*01/J6*02]-[Vκ1-5*03/J1*01] with VH and Vκhypermutation; (b) no clonal relationship between the CLL and myeloma cells that utilized different VHDJH and VκJκ rearrangements [VH3-66*02/3-10*01/J4*03]-[Vκ1-33*01/J2*02] with VH and Vκ hypermutation. To our knowledge, this is the first demonstration of a biclonal CLL with mutated and unmutated clones in the same patient along with a third clonally unrelated B cell malignancy. This result suggests that single cell analysis may be necessary to detect subtle biclonality of CLL that might be associated with a more aggressive phenotype.
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Chen, Weili, Quanzhi Li, Wendy A. Hudson, Ashish Kumar, Nicole Kirchhof e John H. Kersey. "A murine Mll-AF4 knock-in model results in lymphoid and myeloid deregulation and hematologic malignancy". Blood 108, n.º 2 (15 de julho de 2006): 669–77. http://dx.doi.org/10.1182/blood-2005-08-3498.
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The 2 most frequent human MLL hematopoietic malignancies involve either AF4 or AF9 as fusion partners; each has distinct biology but the role of the fusion partner is not clear. We produced Mll-AF4 knock-in (KI) mice by homologous recombination in embryonic stem cells and compared them with Mll-AF9 KI mice. Young Mll-AF4 mice had lymphoid and myeloid deregulation manifest by increased lymphoid and myeloid cells in hematopoietic organs. In vitro, bone marrow cells from young mice formed unique mixed pro-B lymphoid (B220+CD19+CD43+sIgM–, PAX5+, TdT+, IgH rearranged)/myeloid (CD11b/Mac1+, c-fms+, lysozyme+) colonies when grown in IL-7– and Flt3 ligand-containing media. Mixed lymphoid/myeloid hyperplasia and hematologic malignancies (most frequently B-cell lymphomas) developed in Mll-AF4 mice after prolonged latency; long latency to malignancy indicates that Mll-AF4–induced lymphoid/myeloid deregulation alone is insufficient to produce malignancy. In contrast, young Mll-AF9 mice had predominately myeloid deregulation in vivo and in vitro and developed myeloid malignancies. The early onset of distinct mixed lymphoid/myeloid lineage deregulation in Mll-AF4 mice shows evidence for both “instructive” and “noninstructive” roles for AF4 and AF9 as partners in MLL fusion genes. The molecular basis for “instruction” and secondary cooperating mutations can now be studied in our Mll-AF4 model.
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Linden, Michael, Nicole Kirchhof, Cathy Carlson e Brian Van Ness. "Targeted overexpression of Bcl-XL in B-lymphoid cells results in lymphoproliferative disease and plasma cell malignancies". Blood 103, n.º 7 (1 de abril de 2004): 2779–86. http://dx.doi.org/10.1182/blood-2003-10-3399.
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Abstract Multiple myeloma is an incurable malignancy, and there is currently no mouse model that fully recapitulates the development and progression of the disease. We now describe a transgenic mouse that expresses a Bcl-XL transgene under the control of the 3′κ immunoglobulin light chain enhancer, which is most active in murine B cells in late developmental stages. These mice developed nonmalignant plasma cell foci in the bone marrow and soft tissues and hyaline tubular casts in the kidneys. Median survival of the 3′KE/Bcl-XL mice was similar to littermate controls. When the 3′KE/Bcl-XL mouse was crossed to an Eμ/c-Myc transgenic mouse, median survival of double transgenic progeny was 5.5 weeks. Peripheral blood and soft tissues were infiltrated with immature/mature B cells, and plasma cell lesions were identified in the bone marrow of all mice coexpressing Bcl-XL and c-Myc. These B- and plasma cell lesions demonstrated features consistent with malignancy. These results indicate that the 3′κ immunoglobulin light chain enhancer can effectively target expression of Bcl-XL to B cells in late developmental stages, and they provide direct evidence that Bcl-XL can contribute to plasmacytomagenesis. Furthermore, this murine model serves as an important step in developing a novel genetically induced mouse model of plasma cell malignancies exhibiting bone marrow involvement. (Blood. 2004;103:2779-2786)
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Kong, Ling-Yuan, Vaibhav Kapuria, Geoffrey Bartholomeusz, Moshe Talpaz, Waldemar Priebe e Nicholas J. Donato. "Antitumor Activity and Mechanism of Action of a Novel Stat3 Inhibitor, WP1066, Against Human B-Cell Non-Hodgkin’s Lymphoma and Multiple Myeloma." Blood 106, n.º 11 (16 de novembro de 2005): 1489. http://dx.doi.org/10.1182/blood.v106.11.1489.1489.
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Abstract B-cell non-Hodgkin’s lymphomas (B-NHL) have the highest incidence rates among all lymphomas, comprising more than 85% of malignant lymphomas worldwide. Multiple myeloma (MM) is a plasma cell malignancy that affects 14,000 patients per year. Although new therapies have recently been introduced to treat these malignancies, patient survival has not significantly improved, illustrating the need for additional agents that target and suppress this disease. B-cell malignancies over-express c-myc and frequently retain a constitutively activated Stat3, resulting in increased survival gene expression and apoptotic protection. Targeting these transcription factors may reduce apoptotic thresholds and suppress the growth and survival of these malignancies. In this study, we refined and tested the anti-tumor activity of a novel small MW compound discovered by screening a synthetic library for agents that bock Stat3 activation. WP1066, blocked IL-6 mediated Stat3 activation in numerous human B-NHL and MM tumor cells including the Mino, LP, MM-1 and OCI-My5 at low micromolar concentrations. This compound blocks Jak2-depedent cytokine signaling (IL-3, GM-CSF, IL-6) through the rapid (15 min) down-regulation of the upstream tyrosine kinase, Jak2. WP1066 also causes rapid reduction in c-myc in B-cell malignancies but other transcription factors and signaling kinases are not affected by WP1066. The apoptotic effects of WP1066 on B-NHL and MM cells parallel its Stat inhibitory, Jak2 down-regulatory activity. Jak2 down-regulation is not dependent on proteosomal processing but requires activation of a tyrosine phosphatase, suggesting a unique mechanism of WP1066 action. Based on activities described in vitro, we further examined the antitumor activity of WP1066 in a B-NHL xenograft tumor model. Mice were inoculated (i.p.) with 25 × 106 Mino cells (CB17 SCID mice, 4–5 weeks of age) and 13 days later were treated with 10, 20, or 40 mg/kg of WP1066 (i.p.) qd x 5/week for 2 weeks. WP1066 significantly decreased tumor burden and increased the survival of Mino tumor bearing mice treated with 20 or 40 mg/kg of WP1066. These results suggest that WP1066 reduces Stat activation through a unique mechanism and may have therapeutic potential for the treatment of human B-cell non-Hodgkin’s lymphomas and multiple myeloma.
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Das, Manjulika. "Zanubrutinib in B-cell malignancies". Lancet Oncology 20, n.º 9 (setembro de 2019): e470. http://dx.doi.org/10.1016/s1470-2045(19)30523-6.
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Hillis, Jennifer, Michael O’Dwyer e Adrienne M. Gorman. "Neurotrophins and B-cell malignancies". Cellular and Molecular Life Sciences 73, n.º 1 (23 de setembro de 2015): 41–56. http://dx.doi.org/10.1007/s00018-015-2046-4.
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Novero, Aileen, Pavan M. Ravella, Yamei Chen, George Dous e Delong Liu. "Ibrutinib for B cell malignancies". Experimental Hematology & Oncology 3, n.º 1 (2014): 4. http://dx.doi.org/10.1186/2162-3619-3-4.
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Owen, Carolyn J., e Douglas A. Stewart. "Obinutuzumab for B-cell malignancies". Expert Opinion on Biological Therapy 14, n.º 8 (23 de maio de 2014): 1197–205. http://dx.doi.org/10.1517/14712598.2014.922535.
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AbuHilal, Mohanad, Scott Walsh e Neil Shear. "Associated Hematolymphoid Malignancies in Patients With Lymphomatoid Papulosis: A Canadian Retrospective Study". Journal of Cutaneous Medicine and Surgery 21, n.º 6 (14 de junho de 2017): 507–12. http://dx.doi.org/10.1177/1203475417716366.
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Background: Lymphomatoid papulosis is one of the primary cutaneous CD30+ T-cell lymphoproliferative disorders. Although considered a benign disease, lymphomatoid papulosis has been associated potentially with an increased risk of secondary hematolymphoid malignancies. Objective: The aim of this study was to assess the clinical characteristics and histologic subtypes of lymphomatoid papulosis, identify the prevalence and types of secondary hematolymphoid malignancies, and determine the potential risk factors for development of these hematolymphoid malignancies. Methods and Materials: A retrospective chart review was performed for all histologically confirmed cases of lymphomatoid papulosis between 1991 and 2016. Results: Seventy patients with lymphomatoid papulosis were identified. Thirty patients (43%) experienced a secondary hematolymphoid malignancy. Twenty-four (80%) of the hematolymphoid malignancies occurred after the onset of lymphomatoid papulosis. Older age at diagnosis of lymphomatoid papulosis, male sex, histology type B, and the presence of T-cell receptor gene rearrangement are associated with higher risk of developing hematolymphoid malignancy. Conclusion: Lymphomatoid papulosis is associated with increased risk of developing secondary hematolymphoid malignancies, particularly mycosis fungoides and cutaneous anaplastic large cell lymphoma.
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Pongas, Georgios, e Bruce D. Cheson. "PI3K signaling pathway in normal B cells and indolent B-cell malignancies". Seminars in Oncology 43, n.º 6 (dezembro de 2016): 647–54. http://dx.doi.org/10.1053/j.seminoncol.2016.11.011.
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Elsawa, Sherine F., Anne J. Novak, Deanna M. Grote, Steven C. Ziesmer, Thomas E. Witzig, Robert A. Kyle, Stacey R. Dillon, Brandon Harder, Jane A. Gross e Stephen M. Ansell. "B-lymphocyte stimulator (BLyS) stimulates immunoglobulin production and malignant B-cell growth in Waldenström macroglobulinemia". Blood 107, n.º 7 (1 de abril de 2006): 2882–88. http://dx.doi.org/10.1182/blood-2005-09-3552.
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AbstractWaldenström macroglobulinemia (WM) is a serious and frequently fatal B-cell malignancy associated with an elevated monoclonal IgM protein in the serum. Many of the mechanisms leading to this disease are not yet known. B-lymphocyte stimulator (BLyS) is a TNF family member that is critical for maintenance of normal B-cell development and homeostasis. BLyS is overexpressed in a variety of B-cell malignancies and has been shown to inhibit apoptosis in malignant B cells. It also regulates immunoglobulin secretion by normal B cells. To determine the relevance of BLyS in WM, we examined the role of BLyS in WM patient samples. Malignant B cells were found to bind soluble BLyS and variably express the receptors BAFF-R, TACI, and BCMA. We also found expression of BLyS in bone marrow specimens by immunohistochemistry and elevated serum BLyS levels in patients with WM. BLyS, alone or in combination with cytokines that induce immunoglobulin production, was found to increase IgM secretion by malignant B cells. Furthermore, BLyS was found to increase the viability and proliferation of malignant B cells from WM patients. Due to the role of BLyS in WM, strategies to inhibit BLyS may potentially have therapeutic efficacy in these patients.
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Qian, Jin. "Immune escape mechanism of B-cell malignancies on Anti-CD19 Chimeric Antigen Receptor T-cell treatment and solution". E3S Web of Conferences 271 (2021): 03038. http://dx.doi.org/10.1051/e3sconf/202127103038.
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Relapse or refractory B-cell malignancies have been reported in multiple clinical trials after treatment of Anti-CD19 Chimeric Antigen Receptor (CAR) T-cells. Many clinical studies have demonstrated the potential immune escape mechanism for B-cell malignancies like genetic mutation, transcriptional deregulation, lineage switch, loss of CAR T-cells, and trogocytosis. The study of these mechanisms can provide us insights in designs of future immunotherapies regarding both B-cell malignancies and even other solid tumors. The potential solution for the immune escape mechanisms regarding CAR T-cell treatment is engineering multispecific CARs. In this article, I review most of the upto- date immune escape mechanism studies and some multispecific CAR T-cell treatment clinical studies and trials that may prevent the escape route and have to potential to cure B-cell malignancies.
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Brown, Jennifer R., Heather Yeckes, Jonathan W. Friedberg, Donna Neuberg, Helen Kim, Lee M. Nadler e Arnold S. Freedman. "Increasing Incidence of Late Second Malignancies After Conditioning With Cyclophosphamide and Total-Body Irradiation and Autologous Bone Marrow Transplantation for Non-Hodgkin’s Lymphoma". Journal of Clinical Oncology 23, n.º 10 (1 de abril de 2005): 2208–14. http://dx.doi.org/10.1200/jco.2005.05.158.
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Purpose Although the risk of myelodysplastic syndrome (MDS) has been well-described following autologous bone marrow transplantation (ABMT), the risk of solid tumors has been poorly characterized. We report the incidence and outcome of solid tumors at 10-year follow-up in a large cohort of uniformly treated patients who underwent ABMT for non-Hodgkin’s lymphoma (NHL). Patients and Methods Between 1982 and 1997, 605 patients underwent ABMT for B-cell NHL, with uniform conditioning with cyclophosphamide and total-body irradiation followed by reinfusion of autologous bone marrow purged with anti–B-cell monoclonal antibodies. Current information on relapse of disease and second malignancies was obtained via an institutional review board–approved questionnaire sent to the referring oncologists. Results Forty-two solid tumors, six non-MDS hematologic malignancies, 39 nonmelanoma skin cancers, and 68 cases of MDS/acute myelogenous leukemia (AML) were observed at a median follow-up of 9.5 years. A cumulative incidence model using death as a competing risk found that the 10-year incidence of second malignancy is 21%, with 10.0% non-MDS malignancies. The projected incidence of all malignancies at 15 years is 29%. The principal risk factor for second malignancy is increased age at ABMT (P = .0002). In the entire cohort, 9.6% of patients have died of second malignancy. Conclusion Lengthy follow-up demonstrates a significant incidence of second malignancies after ABMT for NHL. Although the incidence of MDS/AML starts to plateau, the incidence of solid tumors continues to rise. Second malignancies are responsible for a significant fraction of overall mortality following ABMT.
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Taghi Khani, Adeleh, Anil Kumar, Kelly Radecki, Sung June Lee, Mary Lorenson, Xiwei Wu, Zhaohui Gu, Ameae Walker e Srividya Swaminathan. "Suppressing Synthesis of the Long Isoform of the Prolactin Receptor Is a Targeted Strategy to Prevent and Treat B Cell Malignancies". Blood 138, Supplement 1 (5 de novembro de 2021): 1135. http://dx.doi.org/10.1182/blood-2021-147055.
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Abstract Rationale B cell malignancies, including leukemia and lymphoma, are high-risk lymphoid neoplasms. B cell malignancies predispose to autoimmune diseases including systemic lupus erythematosus (SLE) which increase the risk of developing these malignancies by >5-fold. Increased prolactin (PRL) expression is known to exacerbate SLE and promote the survival of autoreactive B cells. Furthermore, PRL induces expression of the protooncogenes, MYC and BCL2, in lymphoid tissues. However, whether PRL drives the initiation and maintenance of B cell malignancies was not known. Results We first tested our hypothesis that PRL, specifically signaling through the pro-proliferative and anti-apoptotic long isoform (LF) of the PRL receptor (PRLR), drives the progression of SLE to B cell malignancies. To this end, we knocked down the LF PRLR in MRL-lpr mice predisposed to developing SLE using a splice-modulating oligomer (SMO) that blocks splicing to produce the LF PRLR without affecting the short isoforms. LF PRLR knockdown reduced splenic and circulating B cell numbers in MRL-lpr SLE mice (Fig.1a). Consistent with reduced B cell numbers, BCL2 expression in B cells of SLE mice was suppressed after LF PRLR knockdown, although MYC was unaltered (Fig.1b). By sequencing the immunoglobulin heavy chains (IGH), we compared the composition of the splenic B cell repertoire between control- and LF PRLR SMO-treated SLE mice. Control oligomer treated SLE mice accumulated splenic B cells with long complementary determining region 3 (CDR3) and B cells with non-functional IGH, characteristics of autoreactive B cells. Treatment with the LF PRLR SMO reduced both. We then measured the expression of enzymes known to induce malignant transformation of B cells, namely recombination activating genes 1/2 (RAG1/2) and activation-induced cytidine deaminase (AID), in B cells of SLE mice in controls versus LF PRLR knockdown. Importantly, LF PRLR knockdown significantly reduced RAG1 (Fig.1c) and AID expression in splenic B cells of SLE mice (Fig.1d,e). Our findings thus underscore a causal role for LF PRLR signaling in promoting of malignant transformation of B cells in SLE. Because PRL induces the expression of BCL2 and MYC in lymphocytes, we next determined whether LF PRLR promotes the survival of overt B cell malignancies that overexpress MYC and BCL2, including diffuse large B cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (B-ALL). We observed that B-lymphoblasts expressed significantly higher levels of PRL and the LF PRLR as compared to normal B cells (Fig.1f). We also found that higher expression of PRL at diagnosis predicts poor clinical outcome in DLBCL patients (P=0.0244), and that patients with MYC/BCL2-overexpressing ALLs with a poor prognosis had significantly higher expression of the LF PRLR compared to their MYC lowBCL2 low counterparts (P<0.0001). These observations suggested that LF PRLR may modulate MYC and BCL2 expression. Knockdown of the LF PRLR using the LF PRLR SMO in MYC/BCL2-driven human B cell malignancies killed lymphoblasts and reduced MYC and BCL2 protein levels (Fig.1g). Because we previously showed that MYC-driven lymphoid malignancies are sensitive to natural killer (NK) cell-mediated immune clearance, we also examined whether LF PRLR knockdown synergized with NK cells in killing DLBCL. We found that LF PRLR knockdown enhanced NK cell-mediated killing of B-lymphoblasts (Fig.1h). Of note, no reductions were observed in NK cell viability or MYC levels within NK cells upon LF PRLR knockdown, suggesting that LF PRLR selectively kills B-lymphoblasts without negatively impacting NK homeostasis. Conclusion Our studies identify the specific knockdown of LF PRLR as a potentially safe and targeted strategy to prevent the onset of B cell malignancies in SLE patients and to treat flagrant DLBCL and B-ALL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Greenberg, Zev J., Darlene A. Monlish, Rachel L. Bartnett e Laura G. Schuettpelz. "Regulation of Homeostatic and Malignant B Cell Development By the Tetraspanin CD53". Blood 132, Supplement 1 (29 de novembro de 2018): 3699. http://dx.doi.org/10.1182/blood-2018-99-111957.
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Abstract Acute lymphoblastic leukemia (ALL) is the most frequent pediatric malignancy, most commonly originating from the transformation of progenitor cells of the B cell lineage (B cell precursor-ALL; BCP-ALL). Treatment of patients with high-risk or relapsed disease is difficult and prognosis remains poor in pediatric patients, with an even worse survival rate for adult BCP-ALL. Previous studies have shown an association of enhanced CD53 expression with many B cell malignancies, suggesting upregulation of CD53 may be implicated in carcinogenesis or maintenance of malignant cells. CD53 is a member of the tetraspanin family of transmembrane proteins, classically involved in cell adhesion, proliferation, and survival, and expressed exclusively on hematopoietic cells. While several studies have implicated a role for CD53 in regulating mature B cell proliferation, its role in early B cell development is not yet known. To elucidate the contribution of CD53 to normal and malignant B cell development, we have generated a CD53 knockout mouse. In our CD53-/- mouse, we observe no differences in total white blood cell counts, yet the fraction of peripheral blood B cells is significantly reduced by 31% compared to wild-type (WT) controls (28.3% vs. 19.5%; p<0.005). During homeostatic B lymphopoiesis, CD53 increases through development, beginning at the pre-pro-B cell stage and reaching highest expression on mature B cells. Further investigation into the loss of B cells revealed that immature pre-B cells in the bone marrow and mature B cells in the spleen and lymph nodes are significantly diminished upon loss of CD53, resulting from increased apoptosis in CD53-/- mice. B cell differentiation of CD53-/- hematopoietic stem cells (HSCs) in vitro corroborates the dependence on CD53 for normal differentiation, as CD53-/- cultures have 26% fewer B cells than controls (p=0.033). Investigation into the signaling differences between WT and CD53-/- B cell progenitors by mass cytometry (CyTOF) suggests that decreased PI3K/Akt and MAPK signaling could be driving this loss. With the observed loss of both B cell progenitors and mature B cells in CD53-deficient mice, CD53-/- mice were recently crossed to Eμ-Myc transgenic mice, a model of B-lineage leukemia/lymphoma, to generate WT, CD53-/-, Eμ-Myc+;CD53+/+, and Eμ-Myc+;CD53-/- groups to assess whether loss of CD53 alters the pathology or survival of these mice. As observed in human patients, moribund Eμ-Myc+ mice significantly upregulate CD53 on malignant cells, suggesting a potential role for CD53 during pathogenesis. Ongoing experiments are aimed at elucidating the mechanism by which CD53 promotes homeostatic B cell development and determining the potential of CD53 as a therapeutic target for B lineage malignancies. Disclosures No relevant conflicts of interest to declare.