PML/RAR alpha fusion protein expression in normal human hematopoietic progenitors dictates myeloid commitment and the promyelocytic phenotype

The role of fusion proteins in acute myeloid leukemia (AML) is well recogni zed, but the leukemic target cell and the cellular mechanisms generating th e AML phenotype are essentially unknown, To address this issue, an in vitro model to study the biologic activity of leukemogenic proteins was establis hed. Highly purified human hematopoietic progenitor cells/stem cells (HPC/H SC) in bulk cells or single cells are transduced with retroviral vectors ca rrying cDNA of the fusion protein and the green fluorescent protein (GFP), purified to homogeneity and induced into multilineage or unilineage differe ntiation by specific hematopoietic growth factor (HGF) combinations. Expres sion of PML/RAR alpha fusion protein in human HPC/HSC dictates the acute pr omyelocytic leukemia (APL) phenotype, largely through these previously unre ported effects: rapid induction of HPC/ HSC differentiation to the promyelo cytic stage, followed by maturation arrest, which is abolished by retinoic acid; reprogramming of HPC commitment to preferential granulopoietic differ entiation, irrespective of the HGF stimulus (transduction of single sibling HPC formally demonstrated this effect); HPC protection from apoptosis indu ced by HGF deprivation, A PML/RAR alpha mutated in the co-repressor N-CoR/h istone deacetylase binding region lost these biologic effects, showing that PML/RAR alpha alters the early hematopoietic program through N-CoR-depende nt target gene repression mechanisms, These observations identify the cellu lar mechanism underlying development of the APL phenotype, showing that the fusion protein directly dictates the specific lineage and differentiation stage of leukemic cells. (Blood, 2000;96:1531-1537) (C) 2000 by The America n Society of Hematology.