title: Reduced levels of Hspa9 attenuate Stat5 activation in mouse B cells.
abstract: HSPA9 is located on chromosome 5q31.2 in humans, a region that is commonly deleted in patients with myeloid malignancies [del(5q)], including myelodysplastic syndrome (MDS). HSPA9 expression is reduced by 50% in patients with del(5q)-associated MDS, consistent with haploinsufficient levels. Zebrafish mutants and knockdown studies in human and mouse cells have implicated a role for HSPA9 in hematopoiesis. To comprehensively evaluate the effects of Hspa9 haploinsufficiency on hematopoiesis, we generated an Hspa9 knockout mouse model. Although homozygous knockout of Hspa9 is embryonically lethal, mice with heterozygous deletion of Hspa9 (Hspa9(+/-)) are viable and have a 50% reduction in Hspa9 expression. Hspa9(+/-) mice have normal basal hematopoiesis and do not develop MDS. However, Hspa9(+/-) mice have a cell-intrinsic reduction in bone marrow colony-forming unit-PreB colony formation without alterations in the number of B-cell progenitors in vivo, consistent with a functional defect in Hspa9(+/-) B-cell progenitors. We further reduced Hspa9 expression (<50%) using RNA interference and observed reduced B-cell progenitors in vivo, indicating that appropriate levels (≥50%) of Hspa9 are required for normal B lymphopoiesis in vivo. Knockdown of Hspa9 in an interleukin 7 (IL-7)-dependent mouse B-cell line reduced signal transducer and activator of transcription 5 (Stat5) phosphorylation following IL-7 receptor stimulation, supporting a role for Hspa9 in Stat5 signaling in B cells. Collectively, these data imply a role for Hspa9 in B lymphopoiesis and Stat5 activation downstream of IL-7 signaling.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Kilannin
authors.initials: K
authors.lastname: Krysiak
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Justin F
authors.initials: JF
authors.lastname: Tibbitts
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Shao
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Tuoen
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Ndonwi
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: mjwalter@dom.wustl.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walter
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D015851:Interleukin-7 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D018840:HSP70 Heat-Shock Proteins; C083794:Hspa9 protein, mouse; D015851:Interleukin-7; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor