OVEREXPRESSION OF DR-NM23, A PROTEIN ENCODED BY A MEMBER OF THE NM23 GENE FAMILY, INHIBITS GRANULOCYTE DIFFERENTIATION AND INDUCES APOPTOSIS IN 32DC13 MYELOID CELLS

Chronic myelogenous leukemia evolves in two clinically distinct stages : a chronic and a blast crisis phase. The molecular changes associated with chronic phase to blast crisis transition are largely unknown, We have identified a cDNA clone, DR-nm23, differentially expressed in a blast-crisis cDNA library, which has approximate to 70% sequence simil arity to the putative metastatic suppressor genes, nm23-H1 and nm23-H2 . The deduced amino acid sequence similarity to the proteins encoded b y these two latter genes is approximate to 65% and includes domains an d amino acid residues (the leucine zipper-like and the RGD domain, a s erine and a histidine residue in the NH2- and in the COOH-terminal por tion of the protein, respectively) postulated to be important for nm23 function. DR-nm23 mRNA is preferentially expressed at early stages of myeloid differentiation of highly purified CD34(+) cells, Its constit utive expression in the myeloid precursor 32Dc13 cell line, which is g rowth-factor dependent for both proliferation and differentiation, res ults in inhibition of granulocytic differentiation induced by granuloc yte colony-stimulating factor and causes apoptotic cell death. These r esults are consistent with a role for DR-nm23 in normal hematopoiesis and raise the possibility that its overexpression contributes to diffe rentiation arrest, a feature of blastic transformation in chronic myel ogenous leukemia.