Original Article

BCL-2 Cooperates with Promyelocytic Leukemia Retinoic Acid Receptor Chimeric Protein (PMLRAR) to Block Neutrophil Differentiation and Initiate Acute Leukemia

Correspondence to: Scott C. Kogan, 505 Parnassus Ave., Rm. M-524, University of California at San Francisco, San Francisco, CA 94143-0100. Tel:415-353-1750 Fax:415-353-1106 E-mail:skogan{at}cc.ucsf.edu.

The promyelocytic leukemia retinoic acid receptor (PMLRAR) chimeric protein is associated with acute promyelocytic leukemia (APL). PMLRAR transgenic mice develop leukemia only after several months, suggesting that PMLRAR 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 to initiate leukemia. Evaluation of preleukemic animals showed that whereas PMLRAR alone modestly altered neutrophil maturation, the combination of PMLRAR and BCL-2 caused a marked accumulation of immature myeloid cells in bone marrow. Leukemias developed more rapidly in mice coexpressing PMLRAR and BCL-2 than in mice expressing PMLRAR 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 to initiate APL.

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

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