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Blood, 1 March 2001, Vol. 97, No. 5, pp. 1172-1179
PLENARY PAPER
Expression of DNA methyltransferases DNMT1,
3A, and 3B in normal hematopoiesis and in acute
and chronic myelogenous leukemia
Shin-ichi Mizuno,
Takahito Chijiwa,
Takashi Okamura,
Koichi Akashi,
Yasuyuki Fukumaki,
Yoshiyuki Niho, and
Hiroyuki Sasaki
Aberrant hypermethylation of tumor suppressor genes plays an
important role in the development of many tumors. Recently identified new DNA methyltransferase (DNMT) genes, DNMT3A
and DNMT3B, code for de novo methyltransferases. To
determine the roles of DNMT3A, DNMT3B, as well
as DNMT1, in the development of leukemia, competitive polymerase chain reaction (PCR) assays were performed and the expression levels of DNMTs were measured in normal
hematopoiesis, 33 cases of acute myelogenous leukemia (AML), and 17 cases of chronic myelogenous leukemia (CML). All genes were
constitutively expressed, although at different levels, in T
lymphocytes, monocytes, neutrophils, and normal bone marrow cells.
Interestingly, DNMT3B was expressed at high levels in
CD34+ bone marrow cells but down-regulated in
differentiated cells. In AML, 5.3-, 4.4-, and 11.7-fold mean increases
were seen in the levels of DNMT1, 3A, and
3B, respectively, compared with the control bone marrow
cells. 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 in the levels of DNMT1, 3A, and
3B, respectively. Using methylation-specific PCR, it
was observed that the p15INAK4B gene, a cell
cycle regulator, was methylated in 24 of 33 (72%) cases of AML.
Furthermore, AML cells with methylated
p15INAK4B tended to express higher levels of
DNMT1 and 3B. In conclusion, DNMTs
were substantially overexpressed in leukemia cells in a leukemia type-
and stage-specific manner. Up-regulated DNMTs may contribute to the pathogenesis of leukemia by inducing aberrant regional hypermethylation.
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