Reduced levels of Hspa9 attenuate Stat5 activation in mouse B cells

Kilannin Krysiak, Justin F. Tibbitts, Jin Shao, Tuoen Liu, Matthew Ndonwi, Matthew J. Walter

Research output: Contribution to journalArticle

5 Scopus citations

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 invivo, 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 invivo, indicating that appropriate levels (≥50%) of Hspa9 are required for normal B lymphopoiesis invivo. 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.

Original languageEnglish (US)
Pages (from-to)319-330.e10
JournalExperimental Hematology
Volume43
Issue number4
DOIs
StatePublished - Apr 1 2015
Externally publishedYes

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