AN ACUTE MYELOID-LEUKEMIA GENE, AML1, REGULATES HEMATOPOIETIC MYELOIDCELL-DIFFERENTIATION AND TRANSCRIPTIONAL ACTIVATION ANTAGONISTICALLY BY 2 ALTERNATIVE SPLICED FORMS

The AML1 gene on chromosome 21 is disrupted in the (8;21)(q22;q22) and (3;21)(q26;q22) translocations associated with myelogenous leukemias and encodes a DNA binding protein. From the AML1 gene, two representat ive forms of proteins, AML1a and AML1b, are produced by alternative sp licing, Both forms have a DNA binding domain but, unlike AML1b, AML1a lacks a putative transcriptional activation domain, Here we demonstrat e that overexpressed AML1a totally suppresses granulocytic differentia tion and stimulates cell proliferation in 32Dcl3 murine myeloid cells treated with granulocyte colony-stimulating factor, These effects off AML1a were canceled by the concomitant overexpression of AML1b, Such b iological phenomena could be explained by our observations that (i) AM L1a, which on its own has no effects as a transcriptional regulator, d ominantly suppresses transcriptional activation by AML1b, and (ii) AML 1a exhibits the higher affinity for DNA binding compared with AML1b. T hese antagonistic actions could be important in leukemogenesis and/or myeloid cell differentiation because more than half of myelogenous leu kemia patients showed an increase in the relative amounts of AML1a.