Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia

Aberrant hypermethylation of tumor suppressor genes plays an important role in the development of many tumors. Recently identified new DNA methyltrans ferase (DNMT) genes, DNMT3A and DNMT3B, code for de novo methyltransferases . To determine the roles of DNMT3A, DNMT3B, as well as DNMT1, in the develo pment of leukemia, competitive polymerase chain reaction (PCR) assays were performed and the expression levels of DNMTs were measured in normal hemato poiesis, 33 cases of acute myelogenous leukemia (AML), and 17 cases of chro nic myelogenous leukemia (CML). All genes were constitutively expressed, al though at different levels, in T lymphocytes, monocytes, neutrophils, and n ormal bone marrow cells. Interestingly, DNMT3B was expressed at high levels in CD34(+) bone marrow cells but down-regulated in differentiated cells. I n AML, 5.3-, 4.4-, and 11.7-fold mean increases were seen in the levels df DNMT1, 3A, and 3B, respectively, compared with the control bone marrow cell s. Although CML cells in the chronic phase did not show significant changes , cells in the acute phase showed 3.2-, 4.5-, and 3.4-fold mean increases i n the levels of DNMT1, 3A, and 3B, respectively. Using methylation-specific PCR, it was observed that the p15(INAK4B) gene, a cell cycle regulator, wa s methylated in 24 of 33 (72%) cases of AML. Furthermore, AML cells with me thylated p15(INAK4B) tended to express higher levels of DNMT1 and 3B. In co nclusion, DNMTs were substantially overexpressed in leukemia cells in a leu kemia type- and stage-specific manner. Up-regulated DNMTs may contribute to the pathogenesis of leukemia by inducing aberrant regional hypermethylatio n. hypermethylation.(Blood.2001; 97:1172-1179) (C) 2001 by The American Soc iety of Hematology.