A STAT5 modifier locus on murine chromosome 7 modulates engraftment of hematopoietic stem cells during steady-state hematopoiesis.
Homologous disruption of expression of signal transducer and activator of transcription 5a (STAT5a) and STAT5b (STAT5ab(-/-)) in mice results in hematopoietic stem cells (HSCs) that can engraft irradiated hosts alone but are noncompetitive against wild-type HSCs. To explore mechanisms for this phenotype, we crossed the STAT5 mutations onto an HW80 background congenic to the original C57BL/6 that differs in a small chromosome 7 genomic locus. We previously demonstrated that C57BL/6 or HW80 background STAT5ab(-/-) bone marrow (BM) cells showed equal repopulating function either competitively or noncompetitively in irradiated hosts. However, one intraperitoneal injection of wild-type green fluorescent protein (GFP) transgenic BM cells into unconditioned newborn STAT5ab(-/-) recipients of either background was sufficient for high-level donor engraftment. Furthermore, haploinsufficiency of STAT5 (STAT5ab(+/-)) allowed improved engraftment over wild-type recipients, indicating a dose-dependent requirement for STAT5 activation. In reciprocal experiments, STAT5ab(-/-) BM was transplanted into nonirradiated W/W(v) hosts. In these mice, C57BL/6 STAT5ab(-/-) BM cells were 10-fold more defective in long-term engraftment than control wild-type BM cells and HW80 STAT5ab(-/-) BM cells were 5- to 10-fold more defective than C57BL/6 STAT5ab(-/-) BM cells. Therefore, we conclude that STAT5 plays a critical role during steady-state HSC engraftment and a chromosome 7 modifier locus regulates this activity.
Couldrey
Christine
C
Hematopoiesis Department, Jerome H. Holland Laboratory for the Biomedical Sciences, American Red Cross, Rockville, MD, USA.
Bradley
Heath L
HL
Bunting
Kevin D
KD
D000818:Animals; D000831:Animals, Newborn / Q000235:genetics; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology* / Q000528:radiation effects; D005819:Genetic Markers; D006084:Graft Rejection / Q000235:genetics / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics* / Q000502:physiology / Q000528:radiation effects; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D020297:Mice, Congenic; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000235:genetics* / Q000528:radiation effects; D011828:Radiation Chimera / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics* / Q000502:physiology* / Q000528:radiation effects; D019172:Transplantation Conditioning / Q000379:methods
D004268:DNA-Binding Proteins; D005819:Genetic Markers; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; D015534:Trans-Activators