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Blood, 15 August 2000, Vol. 96, No. 4, pp. 1531-1537
NEOPLASIA
PML/RAR fusion protein expression in normal human
hematopoietic progenitors dictates myeloid commitment and the
promyelocytic phenotype
Francesco Grignani,
Mauro Valtieri,
Marco Gabbianelli,
Vania Gelmetti,
Rosanna Botta,
Luisella Luchetti,
Barbara Masella,
Ornella Morsilli,
Elvira Pelosi,
Paola Samoggia,
Pier Giuseppe Pelicci, and
Cesare Peschle
From the Department of Hematology and Oncology,
Istituto Superiore di Sanità; Rome; the Department of Internal
Medicine and Oncological Sciences, Perugia University, Perugia; the
Department of Experimental Oncology, European Institute of Oncology,
Milan, Italy; and the Kimmel Cancer Center, Thomas
Jefferson University, Philadelphia, PA.
The role of fusion proteins in acute myeloid leukemia (AML) is well
recognized, but the leukemic target cell and the cellular mechanisms
generating the AML phenotype are essentially unknown. To address this
issue, an in vitro model to study the biologic activity of leukemogenic
proteins was established. Highly purified human hematopoietic
progenitor cells/stem cells (HPC/HSC) in bulk cells or single cells are
transduced with retroviral vectors carrying cDNA of the fusion protein
and the green fluorescent protein (GFP), purified to homogeneity and
induced into multilineage or unilineage differentiation by specific
hematopoietic growth factor (HGF) combinations. Expression of
PML/RAR fusion protein in human HPC/HSC dictates the acute
promyelocytic leukemia (APL) phenotype, largely through these
previously unreported effects: rapid induction of HPC/HSC
differentiation to the promyelocytic stage, followed by maturation
arrest, which is abolished by retinoic acid; reprogramming of HPC
commitment to preferential granulopoietic differentiation, irrespective of the HGF stimulus (transduction of single sibling HPC formally demonstrated this effect); HPC protection from
apoptosis induced by HGF deprivation. A PML/RAR mutated in the
co-repressor N-CoR/histone deacetylase binding region lost these
biologic effects, showing that PML/RAR alters the early
hematopoietic program through N-CoR-dependent target gene repression
mechanisms. These observations identify the cellular mechanism
underlying development of the APL phenotype, showing that the fusion
protein directly dictates the specific lineage and differentiation
stage of leukemic cells.
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