P15INK4b gene methylation and myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) are clonal disorders, which frequently undergo leukemic transformation. It was recently shown that the promoter of the p15INK4b but not the p16INK4a gene is frequently and selectively hypermethylated in MDS. The p15INK4b gene is a cyclin dependent kinase inhibitor gene, which is actively transcribed after TGFbeta exposure. Methylation of the p15INK4b gene is significantly correlated with blastic bone marrow involvement, and sequential analyses have shown that methylation increases with disease evolution toward AML. These data strongly suggest that p15INK4b gene methylation is a mechanism allowing leukemic cells to escape to inhibitory signals from the bone marrow environment, however the exact role of p15INK4b gene methylation in disruption of the signal mediated by TGFbeta remains to be investigated.
Quesnel
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B
INSERM U524, IRCL, Lille, France. quesnel@lille.inserm.fr
Fenaux
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P
D000208:Acute Disease; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D001853:Bone Marrow / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics / Q000378:metabolism; D017322:Clinical Trials, Phase II as Topic; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D018450:Disease Progression; D016147:Genes, Tumor Suppressor; D019942:Genes, p16; D006410:Hematopoiesis; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011230:Precancerous Conditions / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000502:physiology; D025521:Tumor Suppressor Proteins
D000964:Antimetabolites, Antineoplastic; C493966:CDKN2B protein, human; D002352:Carrier Proteins; C493968:Cdkn2b protein, mouse; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D000077209:Decitabine; D018844:Cyclin-Dependent Kinases; D001374:Azacitidine