BCL-2 cooperates with promyelocytic leukemia retinoic acid receptor alpha chimeric protein (PMLRARalpha) to block neutrophil differentiation and initiate acute leukemia
| Autor: | Kogan, SC, Brown, DE, Shultz, DB, Truong, BT, Lallemand-Breitenbach, V, Guillemin, MC, Lagasse, E, Weissman, IL, Bishop, JM |
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| Rok vydání: | 2001 |
| Předmět: |
myeloid/leukemia
Neutrophils Recombinant Fusion Proteins Immunology Bone Marrow Cells Chromosome Disorders Apoptosis Acute Cell Transformation acute/leukopoiesis/PML protein/receptors Medical and Health Sciences Transgenic Mice hemic and lymphatic diseases retinoic acid Animals Myeloid Cells Calgranulin A Antigens Fusion Promyelocytic Chromosome Aberrations Oncogene Proteins Neoplastic Leukemia Calcium-Binding Proteins Cell Differentiation Hematopoietic Stem Cells Neoplasm Proteins Proto-Oncogene Proteins c-bcl-2 Differentiation Leukopoiesis Cell Division |
| Zdroj: | The Journal of experimental medicine, vol 193, iss 4 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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