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Journal articles on the topic 'P15/INK4b'

Author: Grafiati

Published: 4 June 2021

Last updated: 1 February 2022

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1

Malumbres, Marcos, Ignacio Pérez De Castro, María I. Hernández, María Jiménez, Teresa Corral, and Angel Pellicer. "Cellular Response to Oncogenic Ras Involves Induction of the Cdk4 and Cdk6 Inhibitor p15INK4b." Molecular and Cellular Biology 20, no. 8 (April 15, 2000): 2915–25. http://dx.doi.org/10.1128/mcb.20.8.2915-2925.2000.

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ABSTRACT The cell cycle inhibitor p15 INK4b is frequently inactivated by homozygous deletion together with p16 INK4a and p19 ARF in some types of tumors. Although the tumor suppressor capability of p15 INK4b is still questioned, it has been found to be specifically inactivated by hypermethylation in hematopoietic malignancies in the absence of p16 INK4a alterations. Here we show that, in vitro, p15 INK4b is a strong inhibitor of cellular transformation by Ras. Surprisingly, p15 INK4b is induced in cultured cells by oncogenic Ras to an extent similar to that of p16 INK4a , and their expression is associated with premature G1 arrest and senescence. Ras-dependent induction of these two INK4 genes is mediated mainly by the Raf-Mek-Erk pathway. Studies with activated and dominant negative forms of Ras effectors indicate that the Raf-Mek-Erk pathway is essential for induction of both the p15 INK4b and p16 INK4a promoters, although other Ras effector pathways can collaborate, giving rise to a stronger response. Our results indicate that p15 INK4b , by itself, is able to stop cell transformation by Ras and other oncogenes such as Rgr (a new oncogene member of the Ral-GDS family, whose action is mediated through Ras). In fact, embryonic fibroblasts isolated from p15 INK4b knockout mice are susceptible to transformation by the Ras or Rgr oncogene whereas wild-type embryonic fibroblasts are not. Similarly, p15 INK4b -deficient mouse embryo fibroblasts are more sensitive than wild-type cells to transformation by a combination of the Rgr and E1A oncogenes. The cell cycle inhibitor p15 INK4b is therefore involved, at least in some cell types, in the tumor suppressor activity triggered after inappropriate oncogenic Ras activation in the cell.

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2

Berg, Tobias, Mahmoud Abdelkarim, Yalin Guo, Manfred Fliegauf, and Michael Lübbert. "AML1/ETO Expresssion in Myeloid Leukemia Cells Is Associated with Enhanced Growth-Inhibitory and P15/INK4b Demethylating Effects of 5-AZA-2′-Deoxycytidine." Blood 104, no. 11 (November 16, 2004): 1165. http://dx.doi.org/10.1182/blood.v104.11.1165.1165.

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Abstract The chromosomal translocation (8;21) results in the expression of the chimeric transcription factor AML1/ETO, the most frequent fusion gene in acute myeloid leukemia. The AML1/ETO fusion protein acts as a transcriptional repressor by mediating epigenetic silencing through recruitment of histone deacetylases. Recently, it was shown that it also mediates gene silencing by associating with DNA methyltransferase (Dnmt). We therefore hypothesized that cells expressing AML1/ETO might be preferentially sensitive to the effects of an inhibitor of Dnmt activity, and might provide a superior model for in vitro demethylation and reactivation of the promoter of the p15/INK4b gene (encoding a negative regulator of the cell cycle) that is frequently methylated and silenced in AML and MDS. The 3 myeloid cell lines Kasumi-1 cells (AML1/ETO-positive), KG-1, and KG-1a (both AML1-ETO-negative) are all bearing a heavily methylated p15/INK4b promoter. They were treated with 50 – 1000 nM 5-aza-2′-deoxycytidine (DAC) for three pulses of 24 hrs each. After 6 days, cell growth and viability were determined and FACS analysis performed after propidium iodide staining. Kasumi-1 showed the highest sensitivity to DAC treatment (growth inhibition at 500 nM DAC: Kasumi-1 74.28 %, KG-1 69.16 %, KG-1a 62.38 %). In addition, DAC treatment (500 nM) led to a stronger increase in the sub-G1 fraction in Kasumi-1 (30.46%) compared to KG-1a (20.84 %). Regional p15/INK4b promoter methylation was assessed quantitatively by bisulfite sequencing of ≤10 individual cloned alleles (containing 21 CpGs residues) for calculation of methylated CpG percentage. The p15/INK4b was highly methylated in all 3 cell lines (methylated CpGs Kasumi-1 95.2 %; KG-1 89.6 %; KG-1a 98.4 % ). In Kasumi-1 cells, treatment with DAC resulted in a striking, dose-dependent regional demethylation of the p15/INK4b promoter (demethylated CpGs at 200 nM of DAC: Kasumi-1 63.8 %, KG-1 48.9 %, KG-1a 9.3 %). No demethylating effect was achieved with equitoxic doses of cytarabine or melphalan. Effective demethylation of the p15/INK4b promoter was associated with p15/INK4b protein induction as determined by Western Blot. Simultaneous treatment with all-trans retinoic acid (ATRA) enhanced the effects of DAC treatment upon growth inhibition, but not upon p15/INK4b induction. U937 cells with ecdysone inducible AML1/ETO expression (Fliegauf et al, Oncogene 2004) were also treated with different doses of DAC. When AML1/ETO was induced, U937 cells showed a higher growth inhibition (U937 + AML1/ETO 38.6 %, U937 - AML1/ETO 18 % at 25 nM) and increase in Sub-G1 (U937 + AML1/ETO 18 %, U937 - AML1/ETO 10.55 % at 100 nM) after treatment with DAC. Our results imply that the growth-inhibitory and proapoptotic effect of DAC on leukemia cells is modulated by AML1/ETO protein (or its target genes). The greater accessibility of the p15/INK4b promoter to the demethylating effect of DAC in AML1/ETO expressing Kasumi-1 cells may also be due to differences in regional chromatin structure. With their differential sensitivity to DAC, the cell lines Kasumi-1 and KG-1a provide a model for the different responses of leukemic blasts to DAC.

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3

Wang, Jishi, Dan Ma, Qin Fang, Ping Wang, Rui Gao, and Jia Sun. "Down-Regulation of HO-1 Promoted Apoptosis Induced By Decitabine Via Increasing p15INK4B Promoter Demethylation in myelodysplastic syndrome." Blood 124, no. 21 (December 6, 2014): 5213. http://dx.doi.org/10.1182/blood.v124.21.5213.5213.

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Abstract Background: Decitabine, reverts hypermethylation of p15INK4B gene in vitro, was used to improves cytopenias and blast excess in over 50% of patients with high-risk myelodys plastic syndrome (MDS). In this study, over-expression of Heme Oxygenase-1(HO-1) was found in MDS cells line SKM-1 cells, and it was closely related to resistance to apoptosis induced by decitabine. Objective: we aimed to further investigated what role of HO-1 exactly played in apoptosis induced by low-does of decitabine in MDS. Method: CCK-8 kits was used to determine the proliferation inhibition of SKM-1 cells. Flow cytometry was used for analyzing cell proliferation rate and apoptosis. The methylation status and expression of P15INK4B in mRNA and protein levels were measured by methylation-specifc polymerase chain reaction (PCR [MSP]). Apoptosis relative factors expression were detected by real-time transcription and Western blot. Result: Up-regulation of HO-1 by transfected it into SKM-1 cells via lenti-virus vector promoted proliferation and protected cells against apoptosis. In contrast, down-regulation of HO-1 enhanced decitabine-induced apoptosis but reduced accumulation of S phase in cell cycle. To explore the mechanism, we detected cell cycle relative protein expression after SKM-1 cells were treated by decitabine in each group. As a result, over-expression of p15 INK4B and CDK4 were observed in SKM-1 cells which HO-1 was inhibited. And p15 INK4B and CDK4 expression-dependent apoptosis was related to caspase3 pathway. Even though HO-1 was silenced, but apoptotic rate never increased as caspase3 pathway was blocked. Conclusion: As we known that p15 INK4B is a keypoint to regulate S phase of cell cycle, in our study, more obvious demethylation of p15 INK4B was seen in group of SKM-1 cells in which HO-1 was down-regulated. It’s equally in patients’ mononuclear cells who suffered from MDS. The worse the prognosis of MDS was judged, the more the mRNA level of HO-1 expressed. In conclusion, over-expression of HO-1 indicated resistance to demethylation of p15 INK4B induced by decitabine. Disclosures No relevant conflicts of interest to declare.

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4

Klangby, Ulf, Ismail Okan, Kristinn P. Magnusson, Martin Wendland, Peter Lind, and Klas G. Wiman. "p16/INK4a and p15/INK4b Gene Methylation and Absence of p16/INK4a mRNA and Protein Expression in Burkitt's Lymphoma." Blood 91, no. 5 (March 1, 1998): 1680–87. http://dx.doi.org/10.1182/blood.v91.5.1680.

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Abstract The fact that the p16/INK4a and p15/INK4b genes are frequently inactivated in human malignancies and that p16/INK4a null mice spontaneously develop B-cell lymphomas prompted us to examine the status of both genes in Burkitt's Lymphoma (BL). We found a low frequency of p16/INK4a and p15/INK4b deletions and mutations in BL cell lines and biopsies. However, p16/INK4a exon 1 was methylated in 17 out of 19 BL lines (89.5%) and in 8 out of 19 BL biopsies (42%) analyzed. p15/INK4b Exon 1 was also methylated, although at a lower frequency. p16/INK4a mRNA was readily detected in BL lines carrying unmethylated p16/INK4a, but not in those carrying methylated p16/INK4a. No p16/INK4a protein was detected in any of the BL lines and biopsies examined. In contrast, only one out of seven lymphoblastoid cell lines (LCLs) examined was methylated in p16/INK4a exon 1, and three out of the six LCLs with unmethylated p16/INK4a expressed detectable levels of p16/INK4a protein. Thus, the frequent p16/INK4a methylation in BL lines correlates with downregulation of p16/INK4a expression, suggesting that exon 1 methylation is responsible for silencing the p16/INK4a gene in BL.

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5

Klangby, Ulf, Ismail Okan, Kristinn P. Magnusson, Martin Wendland, Peter Lind, and Klas G. Wiman. "p16/INK4a and p15/INK4b Gene Methylation and Absence of p16/INK4a mRNA and Protein Expression in Burkitt's Lymphoma." Blood 91, no. 5 (March 1, 1998): 1680–87. http://dx.doi.org/10.1182/blood.v91.5.1680.1680_1680_1687.

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The fact that the p16/INK4a and p15/INK4b genes are frequently inactivated in human malignancies and that p16/INK4a null mice spontaneously develop B-cell lymphomas prompted us to examine the status of both genes in Burkitt's Lymphoma (BL). We found a low frequency of p16/INK4a and p15/INK4b deletions and mutations in BL cell lines and biopsies. However, p16/INK4a exon 1 was methylated in 17 out of 19 BL lines (89.5%) and in 8 out of 19 BL biopsies (42%) analyzed. p15/INK4b Exon 1 was also methylated, although at a lower frequency. p16/INK4a mRNA was readily detected in BL lines carrying unmethylated p16/INK4a, but not in those carrying methylated p16/INK4a. No p16/INK4a protein was detected in any of the BL lines and biopsies examined. In contrast, only one out of seven lymphoblastoid cell lines (LCLs) examined was methylated in p16/INK4a exon 1, and three out of the six LCLs with unmethylated p16/INK4a expressed detectable levels of p16/INK4a protein. Thus, the frequent p16/INK4a methylation in BL lines correlates with downregulation of p16/INK4a expression, suggesting that exon 1 methylation is responsible for silencing the p16/INK4a gene in BL.

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6

Zhang, H., X. Li, L. Ge, J. Yang, J. Sun, and Q. Niu. "Methylation of CpG island of p14(ARK), p15(INK4b) and p16(INK4a) genes in coke oven workers." Human & Experimental Toxicology 34, no. 2 (May 16, 2014): 191–97. http://dx.doi.org/10.1177/0960327114533576.

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To detect the blood genomic DNA methylation in coke oven workers and find a possible early screening index for occupational lung cancer, 74 coke oven workers as the exposed group and 47 water pump workers as the controls were surveyed, and urine samples and peripheral blood mononuclear cells (PBMCs) were collected. Airborne benzo[a]pyrene (B[a]P) levels in workplace and urinary 1-hydroxypyrene (1-OH-Py) levels were determined by high-performance liquid chromatography. DNA damage of PBMCs and the p14(ARK), p15(INK4b) and p16(INK4a) gene CpG island methylation in the promoter region were detected by comet assay and methylation-specific polymerase chain reaction techniques, respectively. Results show that compared with the controls, concentration of airborne B[a]Ps was elevated in the coke plant, and urinary 1-OH-Py’s level and DNA olive tail moment in comet assay were significantly increased in the coke oven workers, and p14(ARK), p15(INK4b) and p16(INK4a) gene methylation rates were also significantly increased. With the working years and urinary 1-OH-Py’s level, the rates of p14(ARK) and p16(INK4a) gene methylation were significantly increased while that of p15(INK4b) gene methylation displayed no statistical change. We conclude that PBMCs’ p14(ARK) and p16(INK4a) gene methylation may be used for screening and warning lung cancer in coke oven workers.

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7

Hamanoue, Satoshi, Miharu Yabe, Hiromasa Yabe, and Takayuki Yamashita. "Hypermethylation of the p15/INK4B Gene in Fanconi Anemia." Blood 104, no. 11 (November 16, 2004): 4296. http://dx.doi.org/10.1182/blood.v104.11.4296.4296.

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Abstract Fanconi anemia (FA) is an inherited bone marrow failure syndrome with multiple complementation groups, characterized by genomic instability and predisposition to MDS and AML. Recent evidence indicates that multiple FA proteins are involved in DNA repair. Thus, increased genetic damage and secondary dysregulation of cell proliferation, differentiation and apoptosis are thought to play important roles in the development of bone marrow failure and subsequent progression to MDS/AML. However, little is known about molecular abnormalities responsible for these hematological disorders. Numerous studies indicated that epigenetic silencing of p15/INK4B, an inhibitor of cyclin-dependent kinases, plays an important role in the pathogenesis of MDS and AML. In the present study, we examined methylation status of 5′ CpG islands of the p15 gene in bone marrow mononuclear cells of FA patients, using methylation-specific PCR (MSP) and combined bisulfite restriction analysis (COBRA). Bone marrow samples were analyzed in 10 patients and serially studied in 4 of them. Hypermethylation of the p15 promoter region was detected in 5 patients (50%). This group included 3 patients with MDS: FA28-1 with refractory anemia (RA), FA87 with RAEB (RA with excess of blasts), and FA88 with later development of RA and progression to RAEB; whereas myelodysplasia was not observed in 2 patients (FA89, FA90). In two cases (FA88, FA90), p15 hypermethylation became negative during their courses, perhaps because of decreased myeloid cells. On the other hand, none of 5 patients without p15 hypermethylation had MDS. These results suggest that p15 hypermethylation is associated with development of MDS and occurs in the early phase of clonal evolution in the disease. Methylation status of p15 may be a useful prognostic factor of FA. Patient Age at onset (year old) Time from onset (month) Cytopenia MDS Cytogenetic abnormalities p15 methylation MSP b p15 methylation COBRA c a siblings, b MSP: methylation specific PCR, c COBRA: combined bisulfite restriction analysis, d ND: not determined FA28-1a 5 128 severe RA − − + 133 severe RA − + ++ FA87 8 252 severe RAEB + + +++ FA88 5 31 moderate − − + +++ 45 severe RA + − − 58 severe RAEB + + + FA89 5 49 mild − − + + 56 severe − − + + FA90 2 2 mild − − + ++ 31 severe − − − − FA28-2a 5 51 mild − − − NDd FA28-3a 3 12 mild − − − NDd FA47 3 15 mild − − − NDd FA68 5 46 moderate − − − NDd FA91 5 129 mild − − − NDd

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8

Le Frère-Belda, M. A., D. Cappellen, A. Daher, S. Gil-Diez-de-Medina, F. Besse, C. C. Abbou, J. P. Thiery, E. S. Zafrani, D. K. Chopin, and F. Radvanyi. "p15 INK4b in bladder carcinomas: decreased expression in superficial tumours." British Journal of Cancer 85, no. 10 (November 2001): 1515–21. http://dx.doi.org/10.1054/bjoc.2001.2106.

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9

Latalova, Pavla, Katerina Smesny Trtkova, Lucie Navratilova, Vlastimil Scudla, and Jiri Minarik. "Analysis of CpG Island DNA Methylation of p15INK4b and RIL in Bone Marrow Samples of Patients with Monoclonal Gammopathies." Blood 124, no. 21 (December 6, 2014): 5174. http://dx.doi.org/10.1182/blood.v124.21.5174.5174.

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Abstract Introduction: Adding a methyl group on the cytosine residues of CpG dinucleotides (CpGs) is a basic phenomenon in DNA methylation. This modification belongs to a group of epigenetic changes that are thought to play one of the key roles in tumor development and progression. DNA hypermethylation occurs mainly in CpG islands of the promoter region in tumor-supressor (TS) genes, which leads to gene silencing. On the other hand, global DNA hypomethylation leads to a genomic instability. Many specific genes are epigenetically changed in individual malignant diseases and these genes are intensively studied by the scientific community. According to the recent research in plasma cell neoplasms, the global genic hypomethylation is predominant in contrast to hypermethylation events. Epigenetic changes of TS genes may worsen prognosis, drug response and microenvironment interaction in multiple myeloma patients. Our aim was to assess the methylation level of the RIL and p15INK4b gene. RIL protein acts as suppressor of cell proliferation and it sensitizes tumor cells to apoptosis, on the other hand, the p15 INK4bplays an important role in inhibiting the cell cycle progression in G1 phase. Methods: Our updated study includes 72 bone marrow aspirate-samples from 68 patients with multiple myeloma (MM) or monoclonal gammopathy of undetermined significance (MGUS). 68 samples were acquired at the time of the diagnosis and four patients with MM were assessed also in remission after chemotherapy. Extracted DNA after bisulfite modification was examined by pyrosequencing method (Pyromark Q96, Qiagen, Germany) and the selected gene regions – RIL promotor, p15INK4b promotor and p15 INK4b exon were analysed. Nine CpGs in the RIL promoter, thirteen CpGs in the p15INK4b promoter and sixteen CpGs in the p15INK4bexon were studied. Average methylation level (MtL) was generated and samples were sorted according to the mean MtL (%) into four groups for the RIL gene (less than 10% MtL, 11-19% MtL, 21-50% and more than 50%). We used commercially available unmethylated DNA and methylated DNA control. Statistical analysis was performed using Pyromark Software and Wilcoxon rank sum test. Results: Out of the four groups for the methylation level of the RIL gene promoter, the groups with 11-19% MtL and 21-50% MtL, detected significant and highly significant differences respectively at both p-values - p-value ≤0.05 and p-value ≤0.01. There were only 2 samples with MtL level over 50% in patients with active MM, precluding valid statistical analysis. In both regions of the p15 INK4b gene, i.e. the promoter and the exon, we did not find any significant differences between the methylation levels - mean MtL ranged from 3% to 6% in p15INK4b promotor and from 3% to 12% in p15 INK4b exon. The time-dependend analysis of the DNA methylation level changes in four patients assessed at the time of diagnosis and in remission of the disease after chemotherapy course revealed a significant decrease of CpGs methylation in all MM patients reaching therapeutic response. Conclusions: Updated data on the epigenetic analysis in patients with monoclonal gammopathies confirmed an important role of the RIL gene in the epigenetic network acting in pathogenesis of MM. The presented results suggest possible prognostic value and therapeutic target in patients with MM. In contrast, the p15 INK4b gene known as a frequent focus of epigenetic modifications in many tumors, did not show statistically significant differences in our study. Our results indicate that for DNA methylation analyses of MM or MGUS patients, the RIL gene could be more useful marker than the p15 INK4b gene. Moreover, the decrease of the methylation level in patients undergoing systemic chemotherapy might be associated with treatment response, suggesting its potential prognostic value. The paper was supported by the grant IGA MZ CR NT14393. Disclosures No relevant conflicts of interest to declare.

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10

Markus, Jan, Matthew T. Garin, Naomi Galili, Azra Raza, Michael J. Thirman, Michelle M. LeBeau, Janet D. Rowley, and Linda Wolff. "Methylation-Independent Silencing of the Tumor Suppressor p15INK4B by CBFb-SMMHC in Acute Myeloid Leukemias with inv(16)." Blood 106, no. 11 (November 16, 2005): 1615. http://dx.doi.org/10.1182/blood.v106.11.1615.1615.

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Abstract The tumor suppressor INK4B(p15) gene is silenced by CpG island hypermethylation in a majority of acute myeloid leukemias (AML). This silencing can be reversed by the treatment with hypomethylating agents, and these agents are currently being tested for therapeutic intervention. So far, it was not investigated whether or not the INK4B is hypermethylated in all cytogenetic subtypes of AML. Our experiments, which compare levels of INK4B methylation in AML with inv(16), t(8:21) and t(15;17) reveal a strikingly low level of methylation in all leukemias with inv(16). This contrasts with significant levels of DNA methylation in a high proportion of the AML from the other two groups. Surprisingly, even though there is a lack of INK4B methylation in samples from patients with inv(16), expression of the gene is very low when compared to that of PBL from healthy individuals or HL60 cells. Subsequent experiments uncovered a novel mechanism to explain the low level of INK4B expression in the inv(16) AMLs. Overexpression of the aberrant chromosome 16-associated gene CBFb-MYH11 in U937 cells results in failure to induce INK4B in response to vitamin D3. Furthermore, CBFb-SMMHC, encoded by CBFb-MYH11 directly represses transcription from an INK4B promoter in a reporter assay. Electromobility shift assays in the AML-derived cell line ME-1 and U937 cells expressing the fusion gene demonstrate that the repression is due to a change in the composition of the complexes recognizing the binding sites for the transcription regulator CBF. In conclusion, we have found that methylation is not the only way to induce silencing of the tumor suppressor p15INK4B in AML. In inv(16)-containing AML, loss of gene expression is accomplished by the direct transcriptional repressor activity of CBFβ-SMMHC.

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11

Datto, M. B., P. P. Hu, T. F. Kowalik, J. Yingling, and X. F. Wang. "The viral oncoprotein E1A blocks transforming growth factor beta-mediated induction of p21/WAF1/Cip1 and p15/INK4B." Molecular and Cellular Biology 17, no. 4 (April 1997): 2030–37. http://dx.doi.org/10.1128/mcb.17.4.2030.

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The adenovirus early gene product E1A is a potent stimulator of cellular proliferation, which when overexpressed can overcome the growth-inhibitory effects of the polypeptide hormone transforming growth factor beta (TGF-beta). The ability of TGF-beta to arrest cell growth in G1 correlates with the transcriptional induction of the cyclin-dependent kinase inhibitors, p15/INK4B and p21/WAF1/Cip1; an inhibition of the G1 cyclin-Cdk complexes; and a maintenance of the retinoblastoma susceptibility gene product, Rb, in a hypophosphorylated state. The ability of E1A to overcome TGF-beta-mediated growth inhibition derives, in part, from its ability to sequester Rb and Rb family members. We report here that E1A also acts upstream of Rb by blocking the TGF-beta-mediated induction of p15 and p21. Consistent with these findings, E1A expression also blocks the ability of TGF-beta to inhibit Cdk2 kinase activity, as well as its ability to hold Rb in a hypophosphorylated state. The effect of E1A on the induction of p15 and p21 is independent of E1A's Rb binding activity. The E1A-mediated decrease in p15 levels is primarily the result of a block at the level of transcriptional activation by TGF-beta. This effect is dependent on E1A's ability to bind p300, one of E1A's target proteins. Thus, the ability of E1A to affect p15 and p21 expression represents an additional possible mechanism by which E1A can circumvent the negative regulation of cell cycle progression.

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Kia, Sima Kheradmand, Marcin M. Gorski, Stavros Giannakopoulos, and C. Peter Verrijzer. "SWI/SNF Mediates Polycomb Eviction and Epigenetic Reprogramming of the INK4b-ARF-INK4a Locus." Molecular and Cellular Biology 28, no. 10 (March 10, 2008): 3457–64. http://dx.doi.org/10.1128/mcb.02019-07.

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ABSTRACT Stable silencing of the INK4b-ARF-INK4a tumor suppressor locus occurs in a variety of human cancers, including malignant rhabdoid tumors (MRTs). MRTs are extremely aggressive cancers caused by the loss of the hSNF5 subunit of the SWI/SNF chromatin-remodeling complex. We found previously that, in MRT cells, hSNF5 is required for p16 INK4a induction, mitotic checkpoint activation, and cellular senescence. Here, we investigated how the balance between Polycomb group (PcG) silencing and SWI/SNF activation affects epigenetic control of the INK4b-ARF-INK4a locus in MRT cells. hSNF5 reexpression in MRT cells caused SWI/SNF recruitment and activation of p15 INK4b and p16 INK4a , but not of p14 ARF . Gene activation by hSNF5 is strictly dependent on the SWI/SNF motor subunit BRG1. SWI/SNF mediates eviction of the PRC1 and PRC2 PcG silencers and extensive chromatin reprogramming. Concomitant with PcG complex removal, the mixed lineage leukemia 1 (MLL1) protein is recruited and active histone marks supplant repressive ones. Strikingly, loss of PcG complexes is accompanied by DNA methyltransferase DNMT3B dissociation and reduced DNA methylation. Thus, various chromatin states can be modulated by SWI/SNF action. Collectively, these findings emphasize the close interconnectivity and dynamics of diverse chromatin modifications in cancer and gene control.

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Camacho, Cristel V., Bipasha Mukherjee, Brian McEllin, Liang-Hao Ding, Burong Hu, Amyn A. Habib, Xian-Jin Xie, et al. "Loss of p15/Ink4b accompanies tumorigenesis triggered by complex DNA double-strand breaks." Carcinogenesis 31, no. 10 (July 26, 2010): 1889–96. http://dx.doi.org/10.1093/carcin/bgq153.

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14

Martinez-Delgado, B., M. Robledo, E. Arranz, A. Osorio, MJ García, G. Echezarreta, C. Rivas, and J. Benitez. "Hypermethylation of p15/ink4b/MTS2 gene is differentially implicated among non-Hodgkin’s lymphomas." Leukemia 12, no. 6 (June 1998): 937–41. http://dx.doi.org/10.1038/sj.leu.2401009.

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15

Saunderson, Emily A., Kevin Rouault-Pierre, John G. Gribben, and Gabriella Ficz. "CRISPR/Cas9-Targeted De Novo DNA Methylation Is Maintained and Impacts the Colony Forming Potential of Human Hematopoietic CD34+ Cells." Blood 134, Supplement_1 (November 13, 2019): 2517. http://dx.doi.org/10.1182/blood-2019-130267.

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Introduction The epigenome is significantly perturbed in hematological malignancies with global DNA hypomethylation and localized hypermethylation of gene promoter CpG islands. Whether specific gene promoter hypermethylation can contribute to the clonal expansion of hematopoietic stem and progenitor cells (HSPCs) in humans by affecting HSPC biology, independently of genetic mutations, has not previously been investigated due to the lack of appropriate tools. We show for the first time that it is possible to target de novo DNA methylation using CRISPR/Cas9 in human CD34+ cells isolated from cord blood (CB). DNA methylation targeted to key cell cycle control gene promoters, INK4b (p15) and ARF (p14), is permanently maintained after dCas9 3A3L degradation and inherited as cells differentiate; inhibiting gene expression and affecting the colony forming potential of CD34+ cells. This demonstrates that specific DNA hypermethylation events can permanently change HSPC biology and impact differentiation, potentially contributing to pre-malignant processes. Methods Human CD34+ HSPCs were isolated from human CB and maintained in liquid culture for 24 hours before nucleofection with mRNA encoding an adapted form of CRISPR/Cas9 which has no nuclease activity (dCas9) and is fused to the catalytic domain of DNA methyltransferase 3A (DNMT3A) and 3L (3A3L). The nucleofection cocktail contained dCas9 3A3L or dCas9 3A3L-mut (lacks methyltransferase activity) and 1 to 3 guide RNAs to target DNA methylation to combinations of the INK4a-ARF-INK4b locus. Cells were then seeded into methylcellulose for a primary colony forming assay (CFU). Colonies were scored after 14 days and cells were either harvested and pooled or individual colonies were picked for single-colony molecular analyses. The DNA was extracted and methylation at the INK4a-ARF-INK4b promoters was quantified using targeted bisulfite sequencing; target gene expression was measured using qPCR. The remaining cells from the primary CFU were re-plated a second (secondary CFU) and third (tertiary CFU) time and colonies were again scored after 14 days. Results and Conclusions Targeting DNA methylation to the INK4a-ARF-INK4b locus or INK4b individually in human CD34+ cells resulted in maintenance of hypermethylation at ARF and/or INK4b gene promoters in individual BFU-E (burst-forming unit-erythroid) and CFU-GM (granulocyte, macrophage) colonies as measured by single-colony targeted bisulfite sequencing after the primary CFU; causing heritable repression of INK4b gene expression in the differentiated cells. Some CpGs were up to 90% methylated, indicating that DNA methylation added at these gene promoters is highly stable as cells differentiate. Hypermethylation of ARF and INK4b was found in some colonies even after the tertiary CFU, demonstrating long-term maintenance of promoter hypermethylation. Unexpectedly, no DNA hypermethylation was detected at INK4a in differentiated cells, but whether this is the case for all subpopulations of HSPCs (i.e. HSCs or lymphoid progenitors) is under investigation. Hypermethylation of INK4b and ARF increased the colony forming potential of CD34+ cells in primary, secondary and tertiary CFUs, compared to the control. Conversely, methylation targeted to INK4b alone did not significantly affect the number of colonies in the first CFU, and decreased the number of colonies in the secondary CFU. This suggests a complex interplay between key cell cycle regulators ARF and INK4b in CD34+ cells and during differentiation which can be disrupted by DNA hypermethylation and gene repression. These findings demonstrate the novel insights we can gain by using CRISPR/Cas9 tools to target DNA methylation and these investigations will reveal how gene promoter hypermethylation can impact HSPC function. Furthermore, studying this locus may uncover an important role for DNA hypermethylation in the development of myeloid malignancies, since INK4b is frequently hypermethylated, but rarely mutated, in myeloid dysplastic/proliferative neoplasms and acute myeloid leukemia. Disclosures Gribben: Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding.

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Tasaka, Taizo, James Berenson, Robert Vescio, Toshiyasu Hirama, Carl W. Miller, Masami Nagai, Jiro Takahara, and H. Phillip Koeffler. "Analysis of the p16 INK4A , p15 INK4B and p18 INK4C genes in multiple myeloma." British Journal of Haematology 96, no. 1 (January 1997): 98–102. http://dx.doi.org/10.1046/j.1365-2141.1997.8552482.x.

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Ye, Fang, and Ningning Li. "Role of p15(INK4B) Methylation in Patients With Myelodysplastic Syndromes: A Systematic Meta-Analysis." Clinical Lymphoma Myeloma and Leukemia 19, no. 6 (June 2019): e259-e265. http://dx.doi.org/10.1016/j.clml.2019.03.013.

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Daskalakis, Michael, Tudung T. Nguyen, Carvell Nguyen, Per Guldberg, Gabriele Köhler, Pierre Wijermans, Peter A. Jones, and Michael Lübbert. "Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2′-deoxycytidine (decitabine) treatment." Blood 100, no. 8 (October 15, 2002): 2957–64. http://dx.doi.org/10.1182/blood.v100.8.2957.

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p16 and p15, 2 inhibitors of cyclin-dependent kinases, are frequently hypermethylated in hematologic neoplasias. Decitabine, or 5-Aza-2′-deoxycytidine, reverts hypermethylation of these genes in vitro, and low-dose decitabine treatment improves cytopenias and blast excess in ∼50% of patients with high-risk myelodysplastic syndrome (MDS). We examined p15and p16 methylation status in bone marrow mononuclear cells from patients with high-risk MDS during treatment with decitabine, using a methylation-sensitive primer extension assay (Ms-SNuPE) to quantitate methylation, and denaturing gradient gel electrophoresis (DGGE) and bisulfite-DNA sequencing to distinguish individually methylated alleles. p15 expression was serially examined in bone marrow biopsies by immunohistochemistry. Hypermethylation in the 5′ p15 gene region was detected in 15 of 23 patients (65%), whereas the 5′ p16 region was unmethylated in all patients. Among 12 patients with hypermethylation sequentially analyzed after at least one course of decitabine treatment, a decrease in p15 methylation occurred in 9 and was associated with clinical response. DGGE and sequence analyses were indicative of hypomethylation induction at individual alleles. Immunohistochemical staining for p15 protein in bone marrow biopsies from 8 patients with p15 hypermethylation revealed low or absent expression in 4 patients, which was induced to normal levels during decitabine treatment. In conclusion, frequent, selectivep15 hypermethylation was reversed in responding MDS patients following treatment with a methylation inhibitor. The emergence of partially demethylated epigenotypes and re-establishment of normal p15 protein expression following the initial decitabine courses implicate pharmacologic demethylation as a possible mechanism resulting in hematologic response in MDS.

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Ishiguro, Atsushi, Takenori Takahata, Masato Saito, Gen Yoshiya, Yoshihiro Tamura, Mutsuo Sasaki, and Akihiro Munakata. "Influence of methylated p15 INK4b and p16 INK4a genes on clinicopathological features in colorectal cancer." Journal of Gastroenterology and Hepatology 21, no. 8 (August 2006): 1334–39. http://dx.doi.org/10.1111/j.1440-1746.2006.04137.x.

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Pacheco, T. R., S. Na, D. A. Norris, W. Weston, and I. H. Maxwell. "Positive regulation of P15 (INK4B), a tumor suppressor gene, in melanoma cell lines by tetracycline." Journal of Dermatological Science 16 (March 1998): S135. http://dx.doi.org/10.1016/s0923-1811(98)83807-3.

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Berg, Tobias, Yalin Guo, Mahmoud Abdelkarim, Manfred Fliegauf, and Michael Lübbert. "Reversal of p15/INK4b hypermethylation in AML1/ETO-positive and -negative myeloid leukemia cell lines." Leukemia Research 31, no. 4 (April 2007): 497–506. http://dx.doi.org/10.1016/j.leukres.2006.08.008.

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Ohsaka, Yasuhito, Shingo Yogosawa, Ryoko Nakanishi, Toshiyuki Sakai, and Hoyoku Nishino. "Polymorphisms in Promoter Sequences of the p15 INK4B and PTEN Genes of Normal Japanese Individuals." Biochemical Genetics 48, no. 11-12 (September 23, 2010): 970–86. http://dx.doi.org/10.1007/s10528-010-9379-3.

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Kordi-Tamandani, Dor Mohammad, Mohammad Ayub Rigi Ladies, Mohammad Hashemi, Abdul-Karim Moazeni-Roodi, Smriti Krishna, and Adam Torkamanzehi. "Analysis of p15 INK4b and p16 INK4a Gene Methylation in Patients with Oral Squamous Cell Carcinoma." Biochemical Genetics 50, no. 5-6 (January 3, 2012): 448–53. http://dx.doi.org/10.1007/s10528-011-9489-6.

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López, Fernando, Teresa Sampedro, José L. Llorente, Mario Hermsen, and César Álvarez-Marcos. "Alterations of p14 ARF , p15 INK4b , and p16 INK4a Genes in Primary Laryngeal Squamous Cell Carcinoma." Pathology & Oncology Research 23, no. 1 (July 4, 2016): 63–71. http://dx.doi.org/10.1007/s12253-016-0083-4.

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Takeuchi, S., CR Bartram, T. Seriu, CW Miller, A. Tobler, JW Janssen, A. Reiter, WD Ludwig, M. Zimmermann, and J. Schwaller. "Analysis of a family of cyclin-dependent kinase inhibitors: p15/MTS2/INK4B, p16/MTS1/INK4A, and p18 genes in acute lymphoblastic leukemia of childhood." Blood 86, no. 2 (July 15, 1995): 755–60. http://dx.doi.org/10.1182/blood.v86.2.755.bloodjournal862755.

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A newly recognized family of proteins that inhibit cyclin-dependent kinases (CDKs) termed cyclin-dependent kinase inhibitors (CDKI) have an important role in regulation of cell-cycle progression. A subfamily of these CDKIs (p15INK4B/MTS2, p16INK4/MTS1, and p18) have a high degree of structural and functional homology and are candidate tumor- suppressor genes. We evaluated the mutational status of the p15, p16, and p18 genes in 103 childhood acute lymphoblastic leukemia (ALL) samples and correlated these results with both their clinical data and additional results concerning their loss of heterozygosity in the region of the p15/p16 genes. Homozygous deletions of the p16 gene occurred extremely frequently in T-ALLs (17/22; 77%), and it was also frequent in precursor-B ALLs (12/81; 15%). Homozygous deletions of the p15 gene were also very frequent in T-ALLs (9/22; 41%), and it occurred in 5 of 81 (6%) precursor-B ALL samples. No deletions of p18 was found in any of the 103 ALL samples. Also, no point mutations of the p15, p16, and p18 genes were detected. We correlated p15/p16 alterations at diagnosis with their clinical characteristics as compared with 2,927 other patients treated similarly. Those with p15/p16 alterations were older; had higher white blood cell counts, often with T-cell ALL phenotype; and more frequently had a mediastinal mass at presentation; but they had the same nonremission, relapse, and survival rates at 5 years as did those patients whose blast cells did not have a p15/p16 deletion. To better understand the extent of alterations affecting chromosome 9p21 (location of the p15/p16 genes), loss of heterozygosity (LOH) was examined at D9S171, which is about 1 megabase proximal to the p15/p16 genes. LOH was detected in 15 of 37 (41%) informative samples. Interestingly, of the 24 informative samples that had no detectable alteration of the p15/p16 genes, 7 samples (29%) had LOH at D9S171. In summary, we show in a very large study that p15 and p16, but not p18, CDKI genes are very frequently altered in ALL; those with p15/p16 alterations are more frequently older children, have higher white blood cells at presentation, and often have a T-cell ALL phenotype. The LOH analysis suggests that another tumor-suppressor gene important in ALL also is present on chromosome 9p21.

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Reynisdottir, I., and J. Massague. "The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2." Genes & Development 11, no. 4 (February 15, 1997): 492–503. http://dx.doi.org/10.1101/gad.11.4.492.

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Kim, Jae-Ryong, Seong-Yong Kim, Bong-Hwan Lee, Sang-Woon Kim, Hong-Jin Kim, and Jung-Hye Kim. "Mutations of CDKN2 (MTS1/p16(INK4A)) and MTS2/p15(INK4B) genes in human stomach, hepatocellular, and cholangio-carcinomas." Experimental & Molecular Medicine 29, no. 3 (September 1997): 151–56. http://dx.doi.org/10.1038/emm.1997.22.

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Guo, Y., M. Engelhardt, D. Wider, M. Abdelkarim, and M. Lübbert. "Effects of 5-aza-2′-deoxycytidine on proliferation, differentiation and p15/INK4b regulation of human hematopoietic progenitor cells." Leukemia 20, no. 1 (November 24, 2005): 115–21. http://dx.doi.org/10.1038/sj.leu.2404019.

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HEIDENREICH, AXEL, JAYA P. GADDIPATI, JUDD W. MOUL, and SHIV SRIVASTAVA. "MOLECULAR ANALYSIS OF P16 Ink4 /CDKN2 AND P15 Ink4B /MTS2 GENES IN PRIMARY HUMAN TESTICULAR GERM CELL TUMORS." Journal of Urology 159, no. 5 (May 1998): 1725–30. http://dx.doi.org/10.1097/00005392-199805000-00101.

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30

Othman, Moneeb A. K., Martina Rincic, Joana B. Melo, Isabel M. Carreira, Eyad Alhourani, Friederike Hunstig, Anita Glaser, and Thomas Liehr. "A Novel Cryptic Three-Way Translocation t(2;9;18)(p23.2;p21.3;q21.33) with Deletion of Tumor Suppressor Genes in 9p21.3 and 13q14 in a T-Cell Acute Lymphoblastic Leukemia." Leukemia Research and Treatment 2014 (October 8, 2014): 1–7. http://dx.doi.org/10.1155/2014/357123.

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Acute leukemia often presents with pure chromosomal resolution; thus, aberrations may not be detected by banding cytogenetics. Here, a case of 26-year-old male diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) and a normal karyotype after standard GTG-banding was studied retrospectively in detail by molecular cytogenetic and molecular approaches. Besides fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and high resolution array-comparative genomic hybridization (aCGH) were applied. Thus, cryptic chromosomal aberrations not observed before were detected: three chromosomes were involved in a cytogenetically balanced occurring translocation t(2;9;18)(p23.2;p21.3;q21.33). Besides a translocation t(10;14)(q24;q11) was identified, an aberration known to be common in T-ALL. Due to the three-way translocation deletion of tumor suppressor genes CDKN2A/INK4A/p16, CDKN2B/INK4B/p15, and MTAP/ARF/p14 in 9p21.3 took place. Additionally RB1 in 13q14 was deleted. This patient, considered to have a normal karyotype after low resolution banding cytogenetics, was treated according to general protocol of anticancer therapy (ALL-BFM 95).

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Markus, Jan, Matthew T. Garin, Juraj Bies, Naomi Galili, Azra Raza, Michael J. Thirman, Michelle M. Le Beau, Janet D. Rowley, P. Paul Liu, and Linda Wolff. "Methylation-Independent Silencing of the Tumor Suppressor INK4b (p15) by CBFβ-SMMHC in Acute Myelogenous Leukemia with inv(16)." Cancer Research 67, no. 3 (February 1, 2007): 992–1000. http://dx.doi.org/10.1158/0008-5472.can-06-2964.

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32

Lübbert, M. "Gene silencing of the p15/INK4B cell-cycle inhibitor by hypermethylation: an early or later epigenetic alteration in myelodysplastic syndromes?" Leukemia 17, no. 9 (September 2003): 1762–64. http://dx.doi.org/10.1038/sj.leu.2403045.

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33

Feng, Xin-Hua, Yao-Yun Liang, Min Liang, Weiguo Zhai, and Xia Lin. "Direct Interaction of c-Myc with Smad2 and Smad3 to Inhibit TGF-β-Mediated Induction of the CDK Inhibitor p15 Ink4B." Molecular Cell 63, no. 6 (September 2016): 1089. http://dx.doi.org/10.1016/j.molcel.2016.08.027.

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34

Hutter, Grit, Miriam Scheubner, Yvonne Zimmermann, Joerg Kalla, Tiemo Katzenberger, Karin Hübler, Sabine Roth, Wolfgang Hiddemann, German Ott, and Martin Dreyling. "Differential effect of epigenetic alterations and genomic deletions of CDK inhibitors [p16(INK4a),p15(INK4b),p14(ARF)] in mantle cell lymphoma." Genes, Chromosomes and Cancer 45, no. 2 (2005): 203–10. http://dx.doi.org/10.1002/gcc.20277.

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35

Wang, Xuan, Yan-Bin Zhu, Hai-Peng Cui, and Ting-Ting Yu. "Aberrant promoter methylation of p15 INK4b and p16 INK4a genes may contribute to the pathogenesis of multiple myeloma: a meta-analysis." Tumor Biology 35, no. 9 (June 8, 2014): 9035–43. http://dx.doi.org/10.1007/s13277-014-2054-2.

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36

Fuchs, Ota, Gabriela Peslova, Dana Provaznikova, and Iuri Marinov. "Increased Expression of Genes for Protooncoproteins SnoN and SnoA in Human Myeloblastic Leukemia ML2 Cells and Resistance of ML2 Cells to Transforming Growth Factor-beta-Induced Growth Arrest." Blood 106, no. 11 (November 16, 2005): 4347. http://dx.doi.org/10.1182/blood.v106.11.4347.4347.

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Abstract Transforming growth factor-beta 1 (TGF-β1) is a multifunctional cytokine involved in a variety of biological processes including development, cell growth, differentiation, apoptosis, cell adhesion, migration, extracellular matrix deposition, and the immune response. The loss of a growth inhibitory response to TGF-β1 is a common feature of many cancers. Human myeloblastic ML2 cells originally obtained from Dr. Minowada (Palumbo A. et al., Blood64, 1059–1063, 1984) were pre-incubated with or without TGF-β1 (5 or 10 ng/ml) or with TGF-β1 antibody for 24 h or 72h and then incubated for further 4 h in the presence of [6-3H] thymidine. TGF-β1 did not decreased the proliferation of ML2 cells measured by incorporation of [6-3H] thymidine into DNA in comparison with control without TGF-β1 or with ML2 cells icubated in the presence of inactivating TGF-β1antibody. The resistance of ML2 cells to TGF-β1-induced growth arrest is not caused by mutation in TGF-β1 receptors (TβRII and ALK5) or Smad4 as we verified by direct sequencing of exons of these genes. After 24 h incubation TGF-β1 increased the levels of mRNA for some target proteins of TGF-β1 -plasminogen activator inhibitor-1, Smad7, SnoN and SnoA (ski novel related gene products), inhibitors of cyclin-dependent kinases (p15/INK4b, p21/WAF1/CIP1) and decreased the levels of mRNA for c-myc, transferrin receptor 1 and inhibitor of differentiation/DNA binding Id1. TGF-β1 did not affect the levels of mRNA for CDC25 phosphatase and RhoA GTPase. The levels of these mRNA were determined by real-time PCR or semiquantitative PCR using specific oligonucleotide primers. The increased expression of SnoN and SnoA genes and the inability of TGF-β1 to cause SnoN degradation may be the cause of ML2 cells resistance to TGF-β1 -induced growth arrest. Antiproliferative genes coding for p15/INK4b, p21/WAF1/CIP1 are not under control of SnoN and SnoA. SnoN (684 aminoacids) and SnoA (415 aminoacids) are the alternatively spliced isoforms. Both these isoforms contain the N-terminal region that is similar to the ski (sloan kettering virus gene product) protooncoprotein. These oncoproteins are incorporated into the histone deacetylase-1 complex through binding to the nuclear corepressor and Smad (Smad2, Smad3 and Smad4) proteins and repress the activity of Smad proteins. The addition of histone deacetylase inhibitors (0.5μM MS-275 or 1mM sodium butyrate) in combination with TGF-β1 (5 ng/ml or 10 ng/ml) in pre-incubation of ML2 cells for 24 h before the incorporation of [6-3H] thymidine into DNA measurement decreased proliferation of ML2 cells in comparison with ML2 cells without additions (control) or ML2 cells with TGF-β1 or histone deacetylase inhibitors. These results support the role of Sno protooncoproteins in resistance of ML2 cells to TGF-β1-induced growth arrest. This study was financially supported by the Internal Grant Agency of the Ministry of Health, Czech Republic (NC/7605-3).

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Kawamata, Norihiko, Carl W. Miller, and H. Phillip Koeffler. "Molecular analysis of a family of cyclin-dependent kinase inhibitor genes (p15/MTS2/INK4b andp18/INK4c) in non-small cell lung cancers." Molecular Carcinogenesis 14, no. 4 (December 1995): 263–68. http://dx.doi.org/10.1002/mc.2940140406.

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do Nascimento Borges, Bárbara, Rommel Mario Rodriguez Burbano, and Maria Lúcia Harada. "Analysis of the methylation patterns of the p16 INK4A , p15 INK4B , and APC genes in gastric adenocarcinoma patients from a Brazilian population." Tumor Biology 34, no. 4 (March 17, 2013): 2127–33. http://dx.doi.org/10.1007/s13277-013-0742-y.

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Frost, Simon J., David J. Simpson, and William E. Farrell. "Decreased proliferation and cell cycle arrest in neoplastic rat pituitary cells is associated with transforming growth factor-β1-induced expression of p15/INK4B." Molecular and Cellular Endocrinology 176, no. 1-2 (May 2001): 29–37. http://dx.doi.org/10.1016/s0303-7207(01)00477-4.

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Hoshino, Koyu, Norio Asou, Toshiya Okubo, Hitoshi Suzushima, Tetsuyuki Kiyokawa, Fumio Kawano, and Hiroaki Mitsuya. "The absence of the p15 INK4B gene alterations in adult patients with precursor B-cell acute lymphoblastic leukaemia is a favourable prognostic factor." British Journal of Haematology 117, no. 3 (May 19, 2002): 531–40. http://dx.doi.org/10.1046/j.1365-2141.2002.03451.x.

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Lehmann, Ulrich, Christiane Dobbelstein, Martin Fenner, Daniel Römermann, Britta Hasemeier, Kathleen Metzig, Doris Steinemann, et al. "Complete cytogenetic remission after decitabine treatment in a patient with secondary AML harbouring high p15 INK4b gene methylation and high global DNA methylation." Annals of Hematology 88, no. 3 (August 13, 2008): 275–77. http://dx.doi.org/10.1007/s00277-008-0584-7.

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42

Malumbres, Marcos, Ignacio Pérez de Castro, Javíer Santos, Raül Pérez-Ollé, José Fernández-Piqueras, and Angel Pellicer. "An AC-repeat adjacent to mouse Cdkn2B allows the detection of specific allelic losses in the p15 INK4b and p16 INK4a tumor suppressor genes." Mammalian Genome 9, no. 3 (March 1998): 183–85. http://dx.doi.org/10.1007/s003359900722.

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43

Heyman, Mats, Teresa Calero Moreno, Yie Liu, Dan Grandér, Omid Rasool, Laura Borgonova‐Brandter, Mats Merup, Stefan Söderhäll, and Stefan Einhorn. "Inverse correlation between loss of heterozygosity of the short arm of chromosome 12 and p15 ink4B /p16 ink4 gene inactivation in childhood acute lymphoblastic leukaemia." British Journal of Haematology 98, no. 1 (July 1997): 147–50. http://dx.doi.org/10.1046/j.1365-2141.1997.1843001.x.

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童, 迎凯. "新抑癌基因<italic>p15<sup>MTS2/INK4B</sup></italic>的研究进展." Chinese Science Bulletin 44, no. 8 (April 1, 1999): 793–99. http://dx.doi.org/10.1360/csb1999-44-8-793.

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45

Yang, Xinmei, Lei Yang, Wanrong Dai, and Bo Ye. "Role of p14^ARF and p15^INK4B promoter methylation in patients with lung cancer: a systematic meta-analysis." OncoTargets and Therapy Volume 9 (November 2016): 6977–85. http://dx.doi.org/10.2147/ott.s117161.

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46

Tien, Hwei-Fang, Jih-Luh Tang, Woei Tsay, Ming-Chi Liu, Fenn-Yu Lee, Chiu-Hwa Wang, Yao-Chang Chen, and Ming-Ching Shen. "Methylation of the p15 INK4B gene in myelodysplastic syndrome: it can be detected early at diagnosis or during disease progression and is highly associated with leukaemic transformation." British Journal of Haematology 112, no. 1 (January 2001): 148–54. http://dx.doi.org/10.1046/j.1365-2141.2001.02496.x.

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Nakamura, Satoki, Lin Tan, Yasuyuki Nagata, Tomonari Takemura, Aya Asahina, Daisuke Yokota, Tomohiro Yagyu, Kiyoshi Shibata, Shinya Fujisawa, and Kazunori Ohnishi. "JmjC-domain containing histone demethylase 1B-mediated p15 Ink4b suppression promotes the proliferation of leukemic progenitor cells through modulation of cell cycle progression in acute myeloid leukemia." Molecular Carcinogenesis 52, no. 1 (November 15, 2011): 57–69. http://dx.doi.org/10.1002/mc.20878.

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48

Choi, Sunga, Tae Woong Kim, and Shivendra V. Singh. "Ginsenoside Rh2-mediated G1 Phase Cell Cycle Arrest in Human Breast Cancer Cells Is Caused by p15 Ink4B and p27 Kip1 -dependent Inhibition of Cyclin-dependent Kinases." Pharmaceutical Research 26, no. 10 (July 23, 2009): 2280–88. http://dx.doi.org/10.1007/s11095-009-9944-9.

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Heidenreich, Birgit, Axel Heidenreich, Andreas Sesterhenn, Shiv Srivastava, Judd W. Moul, and Isabell A. Sesterhenn. "Aneuploidy of Chromosome 9 and the Tumor Suppressor Genes p16^INK4 and p15^INK4B Detected by in situ Hybridization in Locally Advanced Prostate Cancer." European Urology 38, no. 4 (2000): 475–82. http://dx.doi.org/10.1159/000020327.

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50

Kiyota, Akihisa, Satoru Shintani, Mariko Mihara, Yuuji Nakahara, Yoshiya Ueyama, Tomohiro Matsumura, Tetsuhiko Tachikawa, and David T. W. Wong. "Anti-Epidermal Growth Factor Receptor Monoclonal Antibody 225 Upregulates p27^KIP1 and p15^INK4B and Induces G1 Arrest in Oral Squamous Carcinoma Cell Lines." Oncology 63, no. 1 (2002): 92–98. http://dx.doi.org/10.1159/000065726.

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