Mechanisms of MDS/AML molecular pathogenesis in population exposed to radiation

MDS (myelodysplastic syndrome) is a currently increasing hematological abnormality in A-bomb survivors (about 60 years after exposure), and is considered to be a pre-leukemic state since the disease progresses to AML (acute myeloid leukemia). This paper describes the outline of AML1 gene, its genetic alteration in the radiation-exposed population and the mechanism of progression from MDS to AML in AML1 mutants. AML1 (RUNX1) codes an essential transcriptional factor for hemopoiesis. Recently, the point mutation of AML1 has been implicated as a major molecular pathogenesis of MDS/AML as seen by its high frequency in the patients exposed in Hiroshima (36% vs 17% in non-exposed), in a population of Chernobyl nuclear accident, in the patients in Semipalatinsk nuclear test site (39%), and also in patients treated with radio-/chemo-therapy of malignancies like lymphoma. The mutation in MDS/AML patients can roughly classified in 4 types, resulting in proteins with different functions, all of which lack the transcription activating function. In the 4 types, the clinical feature of patients with Ni type (N-terminal, inframe, missense mutation) is known to be marrow hypoplastic MDS/AML, whereas Ct type (C-terminal, truncation, deletion), hyperplastic. Studies in mice and in human cells with transformed muted AML1 genes have shown that pathogenic expression of Ni type AML requires another genetic alteration to promote cell proliferation, and further, that, in Ni and Ct types, progression to AML is dependent on different mechanisms of BMI-1 overexpression for hemopoietic stem cells to proliferate, and of suppression of differentiation of blast cells, respectively. Thus molecular pathogenesis of MDS/AML, refractory hitherto, is being close to elucidation for aiming at its treatment. (K.T)