PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia
Publication Year 2016-01-08, Volume 23, Issue #6, Page 1049-1059
Journal Title
Cell Death Differ
Publication Type
Journal Article
Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis with resultant cytopenias. Increased apoptosis and aberrantly functioning progenitors are thought to contribute to this phenotype. As is the case for other malignancies, overcoming apoptosis is believed to be important in progression toward acute myeloid leukemia (AML). Using the NUP98-HOXD13 (NHD13) transgenic mouse model of MDS, we previously reported that overexpression of the anti-apoptotic protein BCL2, blocked apoptosis and improved cytopenias, paradoxically, delaying leukemic progression. To further understand this surprising result, we examined the role of p53 and its pro-apoptotic effectors, PUMA and NOXA in NHD13 mice. The absence of p53 or PUMA but not NOXA reduced apoptosis and expanded the numbers of MDS-repopulating cells. Despite a similar effect on apoptosis and cell numbers, the absence of p53 and PUMA had diametrically opposed effects on progression to AML: absence of p53 accelerated leukemic progression, while absence of PUMA significantly delayed progression. This may be explained in part by differences in cellular responses to DNA damage. The absence of p53 led to higher levels of gamma-H2AX (indicative of persistent DNA lesions) while PUMA-deficient NHD13 progenitors resolved DNA lesions in a manner comparable to wild-type cells. These results suggest that targeting PUMA may improve the cytopenias of MDS without a detrimental effect on leukemic progression thus warranting further investigation.Cell Death and Differentiation advance online publication, 8 January 2016; doi:10.1038/cdd.2015.159.
WEHI Research Division(s)
Molecular Genetics Of Cancer
PubMed ID
NHMRC Grants
NHMRC/628367 NHMRC/1016701 NHMRC/1020363
Rights Notice
Refer to copyright notice on published article.

Creation Date: 2016-01-29 11:46:03
Last Modified: 2016-06-17 09:29:50
An error has occurred. This application may no longer respond until reloaded. Reload 🗙