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Methylation of the p15INK4b Gene in Myelodysplastic
Syndromes Is Frequent and Acquired During Disease Progression
Bruno Quesnel,
Gaelle Guillerm,
Rodolphe Vereecque,
Eric Wattel,
Claude Preudhomme,
Francis Bauters,
Michael Vanrumbeke, and
Pierre Fenaux
From the Service des maladies du sang and the Laboratoire
d'hematologie, CHU Lille, Lille, France; and INSERM U124, Lille,
France.
p15INK4b gene is an inhibitor of cyclin-dependent kinase
(CDK) 4 and CDK6 whose expression is induced by transforming growth
factor (TGF) . Recent reports suggest frequent methylation of the
p15INK4b gene promoter in leukemias, and it has been
proposed that this methylation could be necessary for leukemic cells to
escape TGF regulation. We investigated the methylation status of
p15INK4b gene in 53 myelodysplastic syndromes (MDS) cases,
including nine that had progressed to acute myeloid leukemia (AML),
using a recently described sensitive method where polymerase chain
reaction (PCR) is preceded by bisulfite modification of DNA
(methylation specific PCR). p15INK4b methylation was
observed in 20 of 53 (38%) of the cases. Twenty of the 24 patients
with greater than 10% bone marrow blasts had p15INK4b
methylation (including all nine patients who had progressed to AML) as
compared with none of MDS patients with <10% bone marrow blasts. No
correlation between karyotypic abnormalities and methylation status was
found. Patients with p15INK4b methylation had a worse
prognosis, but the prognostic significance of p15INK4b
methylation was no more found by multivariate analysis, due to its
strong correlation to the percentage of marrow blasts. In 10 MDS cases,
sequential DNA samples were available. In five of them, methylation of
the p15INK4b gene was detected at leukemic transformation,
but not at diagnosis. Our results showed that methylation of the
p15INK4b gene in MDS is correlated with blastic bone marrow
involvement and increases with disease evolution toward AML. It
suggests that proliferation of leukemic cells might require an escape
of regulation of the G1 phase of the cell cycle, and possibly of TGF
inhibitory effect.
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2985-2990
© 1998 by The American Society of Hematology.
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