Hypermethylation of the P15^INK4b and P16^INK4a in agnogenic myeloid metaplasia (AMM) and AMM in leukaemic transformation

Abstract

Summary. Hypermethylation of p15 and p16 genes was determined in 32 patients with agnogenic myeloid metaplasia(AMM), also known as idiopathic myelofibrosis (MF). These included 10 patients in leukaemic transformation phase. Using polymerase chain reaction‐based methylation analysis assay methods, with substantiation using Southern blot analysis, the study showed no hypermethylation of p15 or p16 genes in the chronic phase of AMM, but p15 gene hypermethylation was found in four patients (40%) and p16 gene hypermethylation in two patients (20%) when they were in leukaemic transformation stage. Furthermore, two of the patients in leukaemic transformation were found to have both p15 and p16 gene hypermethylation, demonstrating possible multiple gene hypermethylation in the same patient. Thus, hypomethylation agents for treating patients with AMM in leukaemic transformation may be appropriate for future trials.

Methylation of the suppressor of cytokine signaling 3 gene (SOCS3) in myeloproliferative disorders

“…Hypermethylation of the ABL1, CALCA, CDH1, CDKN4A, CDKN4B, DAPK1, MGMT, NPM1, TIMP2 and TP73 genes has been reported, albeit usually in low percentages of patients. [45][46][47][48][49][50] No methylation of TGFBR2 CpG islands was detected in PV or IMF. 51,52 Recently, Jost et al 45 reported methylation of SOCS1 in 15% of MPD patients.…”

Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM)

“…7 In MPN, the mechanisms underlying progression to MDS and AML are poorly known, although hypermethylation of p15INK4b and p16INK4a genes has been described during the leukemic evolution of myeloid metaplasia. 8 The hypomethylating agent azacitidine has shown significant survival benefit in higher risk MDS. 9,10 In MPN, azacitidine appears to have limited efficacy in primary myelofibrosis (PMF) and myelofibrosis occurring during the evolution of essential thrombocythemia (ET) or polycythemia vera (PV) despite the induction of global hypomethylation.…”

Emerging treatments for classical myeloproliferative neoplasms

“…Hypermethylation of CpG islands causing inactivation of tumor suppressor genes has been seen in leukemic transformation of MF, 97 but rarely in "chronic phase" MF. 98 Decitabine is effective in MDS and has been used successfully in 1 sporadic case of chronic phase MF.…”