title: PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia.
abstract: 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 γ-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.
authors.affiliation: Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC, Australia.|Department of Clinical Haematology, The Alfred Hospital, Melbourne, VIC, Australia.
authors.forename: A A
authors.initials: AA
authors.lastname: Guirguis
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.
authors.forename: C I
authors.initials: CI
authors.lastname: Slape
authors.affiliation: Bone Marrow Research Laboratories, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: L M
authors.initials: LM
authors.lastname: Failla
authors.affiliation: Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Saw
authors.affiliation: Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC, Australia.
authors.forename: C S
authors.initials: CS
authors.lastname: Tremblay
authors.affiliation: Bioinformatics Platform, Monash University, Clayton, VIC, Australia.|School of Biomedical Sciences, Faculty of Biomedical and Psychological Sciences, Monash University, Clayton, VIC, Australia.
authors.forename: D R
authors.initials: DR
authors.lastname: Powell
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia.|Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia.
authors.forename: F
authors.initials: F
authors.lastname: Rossello
authors.affiliation: Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC, Australia.|Department of Clinical Haematology, The Alfred Hospital, Melbourne, VIC, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Wei
authors.affiliation: Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, VIC, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Strasser
authors.affiliation: Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC, Australia.|Department of Clinical Haematology, The Alfred Hospital, Melbourne, VIC, Australia.
authors.forename: D J
authors.initials: DJ
authors.lastname: Curtis
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D004249:DNA Damage; D004195:Disease Models, Animal; D018450:Disease Progression; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009190:Myelodysplastic Syndromes / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C521093:NUP98-HOXD13 protein, human; D015514:Oncogene Proteins, Fusion; C488588:PUMA protein, mouse; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins