title: Haematopoietic stem cell survival and transplantation efficacy is limited by the BH3-only proteins Bim and Bmf.
abstract: Anti-apoptotic Bcl-2 family members are critical for the regulation of haematopoietic stem and progenitor cell (HSPC) survival. Little is known about the role of their pro-apoptotic antagonists, i.e. 'BH3-only' proteins, in this cell compartment. Based on the analysis of cytokine deprivation-induced changes in mRNA expression levels of Bcl-2 family proteins, we determined the consequences of BH3-only protein depletion on HSPC survival in culture and, for selected candidates, on engraftment in vivo. Thereby, we revealed a critical role for Bim and Bmf as regulators of HSPC dynamics both during early engraftment and long-term reconstitution. HSPCs derived from wild-type donors were readily displaced by Bim- or Bmf-deficient or Bcl-2-overexpressing HSPCs as early as 10 days after engraftment. Moreover, in the absence of Bim, significantly lower numbers of transplanted HSPCs were able to fully engraft radio-depleted recipients. Finally, we provide proof of principle that RNAi-based reduction of BIM or BMF, or overexpression of BCL-2 in human CD34(+)  cord blood cells may be an attractive therapeutic option to increase stem cell survival and transplantation efficacy.
authors.affiliation: Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria. verena.labi@mdc-berlin.de
authors.forename: Verena
authors.initials: V
authors.lastname: Labi
authors.forename: Daniela
authors.initials: D
authors.lastname: Bertele
authors.forename: Claudia
authors.initials: C
authors.lastname: Woess
authors.forename: Denise
authors.initials: D
authors.lastname: Tischner
authors.forename: Florian J
authors.initials: FJ
authors.lastname: Bock
authors.forename: Sven
authors.initials: S
authors.lastname: Schwemmers
authors.forename: Heike L
authors.initials: HL
authors.lastname: Pahl
authors.forename: Stephan
authors.initials: S
authors.lastname: Geley
authors.forename: Mirjam
authors.initials: M
authors.lastname: Kunze
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Niemeyer
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.forename: Miriam
authors.initials: M
authors.lastname: Erlacher
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C435486:Bmf protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins