Inhibition of apoptosis by BCL2 prevents leukemic transformation of a murine myelodysplastic syndrome

Slape, Christopher I., Saw, Jesslyn, Jowett, Jeremy B. M., Aplan, Peter D., Strasser, Andreas, Jane, Stephen M. and Curtis, David J. (2012) Inhibition of apoptosis by BCL2 prevents leukemic transformation of a murine myelodysplastic syndrome. Blood, 120 12: 2475-2483. doi:10.1182/blood-2012-05-430736

Author Slape, Christopher I.
Saw, Jesslyn
Jowett, Jeremy B. M.
Aplan, Peter D.
Strasser, Andreas
Jane, Stephen M.
Curtis, David J.
Title Inhibition of apoptosis by BCL2 prevents leukemic transformation of a murine myelodysplastic syndrome
Journal name Blood   Check publisher's open access policy
ISSN 0006-4971
Publication date 2012-09-20
Year available 2012
Sub-type Article (original research)
DOI 10.1182/blood-2012-05-430736
Open Access Status Not yet assessed
Volume 120
Issue 12
Start page 2475
End page 2483
Total pages 9
Place of publication Washington, DC, United States
Publisher American Society of Hematology
Language eng
Formatted 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.
Keyword Hematology
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 628367
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Chemistry and Molecular Biosciences
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