BCL-2 cooperates with promyelocytic leukemia retinoic acid receptor alpha chimeric protein (PMLRARalpha) to block neutrophil differentiation and initiate acute leukemia.
The promyelocytic leukemia retinoic acid receptor alpha (PMLRARalpha) chimeric protein is associated with acute promyelocytic leukemia (APL). PMLRARalpha transgenic mice develop leukemia only after several months, suggesting that PMLRARalpha 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 PMLRARalpha to initiate leukemia. Evaluation of preleukemic animals showed that whereas PMLRARalpha alone modestly altered neutrophil maturation, the combination of PMLRARalpha and BCL-2 caused a marked accumulation of immature myeloid cells in bone marrow. Leukemias developed more rapidly in mice coexpressing PMLRARalpha and BCL-2 than in mice expressing PMLRARalpha 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 PMLRARalpha to initiate APL.
Kogan
S C
SC
Department of Laboratory Medicine, University of California at San Francisco, San Francisco, California 94143, USA. skogan@cc.ucsf.edu
Brown
D E
DE
Shultz
D B
DB
Truong
B T
BT
Lallemand-Breitenbach
V
V
Guillemin
M C
MC
Lagasse
E
E
Weissman
I L
IL
Bishop
J M
JM
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology; D002135:Calcium-Binding Proteins / Q000235:genetics; D040501:Calgranulin A; D002454:Cell Differentiation; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002869:Chromosome Aberrations; D025063:Chromosome Disorders; D006412:Hematopoietic Stem Cells; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D019891:Leukopoiesis; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology; D009363:Neoplasm Proteins / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D000943:Antigens, Differentiation; D002135:Calcium-Binding Proteins; D040501:Calgranulin A; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein