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Prepublished online as a Blood First Edition Paper on September 22, 2003; DOI 10.1182/blood-2003-07-2249.

Submitted July 7, 2003
Accepted September 13, 2003
Aberrant methylation of DAP-kinase in therapy-related acute myeloid leukemia and myelodysplastic syndromes
Maria Teresa Voso*, Alessandra Scardocci, Francesco Guidi, Gina Zini, Antonella Di Mario, Livio Pagano, Stefan Hohaus, and Giuseppe Leone
Institute of Hematology, Universita' Cattolica S. Cuore, Rome, Italy
* Corresponding author; email: mtvoso{at}rm.unicatt.it.
Death-associated protein kinase (DAP-kinase), a pro-apoptotic serine/threonine kinase, is a candidate tumor suppressor gene. We studied the methylation status of DAP-kinase of 194 bone marrow samples from 160 patients with acute myeloid leukemia (AML) and 34 with a myelodysplastic syndrome (MDS) at the time of initial diagnosis by PCR. Hypermethylation of DAP-kinase was present in 27.5% (44/160) of AML, and in 47% (16/34) of MDS specimens and significantly correlated to loss of DAP-kinase expression (p=0.008). It was significantly more frequent in AML secondary to therapy for other malignancies (s-AML, 14/29, 48.3%), as compared to de novo AML (30/131, 22.9%, p=0.01). DAP-kinase hypermethylation in AML was associated to myelodysplastic changes in the bone marrow at the time of the initial diagnosis (p=0.002), and to the presence of cytogenetic abnormalities (p=0.02). Alteration in the apoptotic response due to the loss of DAP-kinase function may be an early event in the transformation pathway to secondary leukemia via myelodysplasia.

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