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BCL-2 cooperates with promyelocytic leukemia retinoic acid receptor alpha chimeric protein (PMLRARalpha) to block neutrophil differentiation and initiate acute leukemia.

Kogan SC, Brown DE, Shultz DB, Truong BT, Lallemand-Breitenbach V, Guillemin MC, Lagasse E, Weissman IL, Bishop JM - J. Exp. Med. (2001)

Bottom Line: The promyelocytic leukemia retinoic acid receptor alpha (PMLRARalpha) chimeric protein is associated with acute promyelocytic leukemia (APL).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine, University of California at San Francisco, San Francisco, California 94143, USA. skogan@cc.ucsf.edu

ABSTRACT
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.

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PMLRARα and PMLRARα/BCL-2 leukemic mice are anemic, thrombocytopenic, and have bone marrow that is filled with promyelocytes. (A) Peripheral blood. Results are displayed as in the legend to Fig. 1 A. Adult controls, n = 7; PMLRARα leukemia, n = 10; PMLRARα/BCL-2 leukemia, n = 10. White blood cell count (WBC) was not significantly different among the groups. Hemoglobin (HGB) and platelet count (PLT) were reduced in leukemic mice (P < 0.00001). (B) Bone marrow. Results are displayed as in the legend to Fig. 1 C. Adult controls, n = 7; PMLRARα leukemia, n = 6; PMLRARα/BCL-2 leukemia, n = 6. All values were significantly different in leukemic mice compared with controls (P < 0.00001 to P = 0.002), but were not significantly different between PMLRARα and PMLRARα/BCL-2 leukemias.
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Figure 4: PMLRARα and PMLRARα/BCL-2 leukemic mice are anemic, thrombocytopenic, and have bone marrow that is filled with promyelocytes. (A) Peripheral blood. Results are displayed as in the legend to Fig. 1 A. Adult controls, n = 7; PMLRARα leukemia, n = 10; PMLRARα/BCL-2 leukemia, n = 10. White blood cell count (WBC) was not significantly different among the groups. Hemoglobin (HGB) and platelet count (PLT) were reduced in leukemic mice (P < 0.00001). (B) Bone marrow. Results are displayed as in the legend to Fig. 1 C. Adult controls, n = 7; PMLRARα leukemia, n = 6; PMLRARα/BCL-2 leukemia, n = 6. All values were significantly different in leukemic mice compared with controls (P < 0.00001 to P = 0.002), but were not significantly different between PMLRARα and PMLRARα/BCL-2 leukemias.

Mentions: Mice reconstituted with PMLRARα or PMLRARα/BCL-2 bone marrow were observed for the development of leukemia. Leukemias developed more rapidly in mice coexpressing PMLRARα and BCL-2 than in mice expressing PMLRARα alone (median time to leukemia 127 vs. 257 d; Fig. 3). All mice reconstituted with doubly transgenic bone marrow succumbed to leukemia by 196 d of age. Similar to the leukemias that arose from singly transgenic PMLRARα mice, leukemias arising from PMLRARα/BCL-2 doubly transgenic mice were characterized by anemia and thrombocytopenia, and by bone marrow that was effaced by cells at the blast-promyelocyte stage of differentiation (Fig. 4 and Fig. 5 A). Although there was a trend towards increased peripheral white blood cell counts in PMLRARα/BCL-2 leukemias, this trend was not statistically significant (P > 0.05).


BCL-2 cooperates with promyelocytic leukemia retinoic acid receptor alpha chimeric protein (PMLRARalpha) to block neutrophil differentiation and initiate acute leukemia.

Kogan SC, Brown DE, Shultz DB, Truong BT, Lallemand-Breitenbach V, Guillemin MC, Lagasse E, Weissman IL, Bishop JM - J. Exp. Med. (2001)

PMLRARα and PMLRARα/BCL-2 leukemic mice are anemic, thrombocytopenic, and have bone marrow that is filled with promyelocytes. (A) Peripheral blood. Results are displayed as in the legend to Fig. 1 A. Adult controls, n = 7; PMLRARα leukemia, n = 10; PMLRARα/BCL-2 leukemia, n = 10. White blood cell count (WBC) was not significantly different among the groups. Hemoglobin (HGB) and platelet count (PLT) were reduced in leukemic mice (P < 0.00001). (B) Bone marrow. Results are displayed as in the legend to Fig. 1 C. Adult controls, n = 7; PMLRARα leukemia, n = 6; PMLRARα/BCL-2 leukemia, n = 6. All values were significantly different in leukemic mice compared with controls (P < 0.00001 to P = 0.002), but were not significantly different between PMLRARα and PMLRARα/BCL-2 leukemias.
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Figure 4: PMLRARα and PMLRARα/BCL-2 leukemic mice are anemic, thrombocytopenic, and have bone marrow that is filled with promyelocytes. (A) Peripheral blood. Results are displayed as in the legend to Fig. 1 A. Adult controls, n = 7; PMLRARα leukemia, n = 10; PMLRARα/BCL-2 leukemia, n = 10. White blood cell count (WBC) was not significantly different among the groups. Hemoglobin (HGB) and platelet count (PLT) were reduced in leukemic mice (P < 0.00001). (B) Bone marrow. Results are displayed as in the legend to Fig. 1 C. Adult controls, n = 7; PMLRARα leukemia, n = 6; PMLRARα/BCL-2 leukemia, n = 6. All values were significantly different in leukemic mice compared with controls (P < 0.00001 to P = 0.002), but were not significantly different between PMLRARα and PMLRARα/BCL-2 leukemias.
Mentions: Mice reconstituted with PMLRARα or PMLRARα/BCL-2 bone marrow were observed for the development of leukemia. Leukemias developed more rapidly in mice coexpressing PMLRARα and BCL-2 than in mice expressing PMLRARα alone (median time to leukemia 127 vs. 257 d; Fig. 3). All mice reconstituted with doubly transgenic bone marrow succumbed to leukemia by 196 d of age. Similar to the leukemias that arose from singly transgenic PMLRARα mice, leukemias arising from PMLRARα/BCL-2 doubly transgenic mice were characterized by anemia and thrombocytopenia, and by bone marrow that was effaced by cells at the blast-promyelocyte stage of differentiation (Fig. 4 and Fig. 5 A). Although there was a trend towards increased peripheral white blood cell counts in PMLRARα/BCL-2 leukemias, this trend was not statistically significant (P > 0.05).

Bottom Line: The promyelocytic leukemia retinoic acid receptor alpha (PMLRARalpha) chimeric protein is associated with acute promyelocytic leukemia (APL).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine, University of California at San Francisco, San Francisco, California 94143, USA. skogan@cc.ucsf.edu

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus