THE PEBP2-BETA-MYH11 FUSION CREATED BY INV(16)(P13-Q22) IN MYELOID-LEUKEMIA IMPAIRS NEUTROPHIL MATURATION AND CONTRIBUTES TO GRANULOCYTIC DYSPLASIA

Chromosomal translocations involving the genes encoding the alpha and beta subunits of the Pebp2/Cbf transcription factor have been associat ed with human acute myeloid leukemia and the preleukemic condition, my elodysplasia, Inv(16)(p13;q22) fuses the gene encoding the beta subuni t of Pebp2 to the MYH11 gene encoding a smooth muscle myosin heavy cha in (Smmhc), To examine the effect of the inv(16)(p13;q22) on myelopoie sis, we used the hMRP8 promoter element to generate transgenic mice ex pressing the Pebp2 beta Smmhc chimeric fusion protein in myeloid cells . Neutrophil maturation was impaired in PEBP2 beta MYH11 transgenic mi ce. Although the transgenic mice had normal numbers of circulating neu trophils, their bone marrow contained increased numbers of immature ne utrophilic cells, which exhibited abnormal characteristics. In additio n, PEBP2 beta MYH11 inhibited neutrophilic differentiation in colonies derived from hematopoietic progenitors. Coexpression of both PEBP2 be ta MYH11 and activated NRAS induced a more severe phenotype characteri zed by abnormal nuclear morphology indicative of granulocytic dysplasi a, These results show that PEBP2 beta MYH11 can impair neutrophil deve lopment and provide evidence that alterations of Pebp2 can contribute to the genesis of myelodysplasia.