Inhibition of apoptosis by BCL2 prevents leukemic transformation of a murine myelodysplastic syndrome
- Author(s)
- Slape, CI; Saw, J; Jowett, JBM; Aplan, PD; Strasser, A; Jane, SM; Curtis, DJ;
- Details
- Publication Year 2012-09-20,Volume 120,Issue #12,Page 2475-2483
- Journal Title
- BLOOD
- Publication Type
- Journal Article
- Abstract
- Programmed cell death or apoptosis is a prominent feature of low-risk myelodysplastic syndromes (MDS), although the underlying mechanism remains controversial. High-risk MDS have less apoptosis associated with increased expression of the prosurvival BCL2-related proteins. To address the mechanism and pathogenic role of apoptosis and BCL2 expression in MDS, we used a mouse model resembling human MDS, in which the fusion protein NUP98-HOXD13 (NHD13) of the chromosomal translocation t(2;11)(q31;p15) is expressed in hematopoietic cells. Hematopoietic stem and progenitor cells from 3-month-old mice had increased rates of apoptosis associated with increased cell cycling and DNA damage. Gene expression profiling of these MDS progenitors revealed a specific reduction in Bcl2. Restoration of Bcl2 expression by a BCL2 transgene blocked apoptosis of the MDS progenitors, which corrected the macrocytic anemia. Blocking apoptosis also restored cell-cycle quiescence and reduced DNA damage in the MDS progenitors. We expected that preventing apoptosis would accelerate malignant transformation to acute myeloid leukemia (AML). However, contrary to expectations, preventing apoptosis of premalignant cells abrogated transformation to AML. In contrast to the current dogma that overcoming apoptosis is an important step toward cancer, this work demonstrates that gaining a survival advantage of premalignant cells may delay or prevent leukemic progression. (Blood. 2012;120(12):2475-2483)
- Publisher
- AMER SOC HEMATOLOGY
- Keywords
- HEMATOPOIETIC STEM-CELLS; TRANSGENIC MICE DEVELOP; FAS-INDUCED APOPTOSIS; MOUSE MODEL; BETA-CELLS; DEATH; DISEASE; EXPRESSION; PROTEINS; CANCER
- Research Division(s)
- Molecular Genetics Of Cancer
- Link To PubMed Central Version
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448259/
- Publisher's Version
- https://doi.org/10.1182/blood-2012-05-430736
- Open Access at Publisher's Site
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- © 2012 by The American Society of Hematology
Creation Date: 2012-09-20 12:00:00