The Journal of Experimental Medicine
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Published online 19 February 2001.
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© The Rockefeller University Press, 0022-1007/2001/2/531/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 4, February 19, 2001 531-544

Original Article

Bcl-2 Cooperates with Promyelocytic Leukemia Retinoic Acid Receptor {alpha} Chimeric Protein (Pmlrar{alpha}) to Block Neutrophil Differentiation and Initiate Acute Leukemia

Scott C. Kogana, Diane E. Brownc, David B. Shultza, Bao-Tran H. Truonga, Valerie Lallemand-Breitenbachd, Marie-Claude Guillemind, Eric Lagassee, Irving L. Weissmanf, and J. Michael Bishopb

a Department of Laboratory Medicine, University of California at San Francisco, San Francisco, California 94143
b G.W. Hooper Research Foundation and Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, California 94143
c St. Louis Children's Hospital, St. Louis, Missouri 63110
d Centre National Recherche Scientifique, UPR 9051, Hópital Saint-Louis, 75475 Paris Cedex 10, France
e StemCell Incorporated, Sunnyvale, California 94068
f Department of Pathology, Stanford University, Stanford, California 94305
505 Parnassus Ave., Rm. M-524, University of California at San Francisco, San Francisco, CA 94143-0100.415-353-1106415-353-1750

skogan{at}cc.ucsf.edu

The promyelocytic leukemia retinoic acid receptor {alpha} (PMLRAR{alpha}) chimeric protein is associated with acute promyelocytic leukemia (APL). PMLRAR{alpha} transgenic mice develop leukemia only after several months, suggesting that PMLRAR{alpha} does not by itself confer a fully malignant phenotype. Suppression of apoptosis can have a central role in tumorigenesis; therefore, we assessed whether BCL-2 influenced the ability of PMLRAR{alpha} to initiate leukemia. Evaluation of preleukemic animals showed that whereas PMLRAR{alpha} alone modestly altered neutrophil maturation, the combination of PMLRAR{alpha} and BCL-2 caused a marked accumulation of immature myeloid cells in bone marrow. Leukemias developed more rapidly in mice coexpressing PMLRAR{alpha} and BCL-2 than in mice expressing PMLRAR{alpha} alone, and all mice expressing both transgenes succumbed to leukemia by 7 mo. Although both preleukemic, doubly transgenic mice and leukemic animals had abundant promyelocytes in the bone marrow, only leukemic mice exhibited thrombocytopenia and dissemination of immature cells. Recurrent gain of chromosomes 7, 8, 10, and 15 and recurrent loss of chromosome 2 were identified in the leukemias. These chromosomal changes may be responsible for the suppression of normal hematopoiesis and dissemination characteristic of the acute leukemias. Our results indicate that genetic changes that inhibit apoptosis can cooperate with PMLRAR{alpha} to initiate APL.

Key Words: leukemia • myeloid/leukemia • promyelocytic • acute/leukopoiesis/PML protein/receptors • retinoic acid

Abbreviations used in this paper: 7-AAD, 7-amino actinomycin D; AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; PML, promyelocytic leukemia; RAR{alpha}, retinoic acid receptor {alpha}; tRA, all-trans retinoic acid.

© 2001 The Rockefeller University Press


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