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

Abstract

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

Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation

“…26,27 On the other hand, overexpression of Bcl-2 and Bcl-XL proteins with known antiapoptotic functions, promotes tumor development in pancreatic beta-cells, in lymphoid cells and in myeloid cells. [28][29][30] In the present study, we addressed the tissue/cell-specific effects of BID in HCC development. We found a profound decrease in HCC development induced by DEN administration, and as early as 48 h after high-dose DEN injection we found a marked decrease in hepatocyte proliferation markers.…”

How One Thing Led to Another

“…We thought if we generated a mouse whose granulocytes do not die on time and crossed it to CF mice, we might get clues as to how to ameliorate the disease and perhaps how to treat it with HSC transplantation from healthy donors. We cloned the upstream region of mrp8 and used it to drive human Bcl2 in transgenic mice (209 (212,213), but also triggered a variety of studies in the lab (152,201,(214)(215)(216)(217)(218)(219)(220)(221)(222)(223). For example, we demonstrated a number of developmental events wherein cytokine instructions acted by keeping a cell type alive to follow its intrinsic developmental progression, and the signal transduction pathway, e.g., monocytes to macrophages and osteoclasts in M-CSF-deficient osteopetrotic mice, could be replaced by stage-specific expression of bcl2 (52,214).…”

Review: genetic models of acute myeloid leukaemia

“…Penetrance in this model was reported only at 15% with not all animals bearing mutation exhibiting AML. Conversely, doubly transgenic PML/RARa-Bcl-2 mice exhibited marked accumulation of immature myeloid progenitors and leukaemic development, in comparison to singly transgenic hMRP8-PML/RARa mice, with all mice capitulating to acute leukaemia by 7 months (Kogan et al, 2001). Cross-breeding LSL-K-ras with cathepsin G-PML-RAR mice (Chan et al, 2006) developed APL-like disease with a penetrance of 69% and average disease latency of 39 days, with the remaining mice developing a myeloproliferative disease.…”