Vacuolar Protein Sorting-Associated Protein 72 (VPS72) is Required for Hematopoietic Stem Cell Development

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B883
Abstract ID: 4931

Presenting Author:
Kalpana Subedi , Research Lab Associate III at Henry Ford Hlth., Henry Ford Cancer Inst., Henry Ford Hlth.

Abstract:

VPS72 incorporates H2AZ to nucleosome leading to transcription regulation. The objective of this study is to characterize the role of VPS72 in hematopoietic stem cells (HSC) development. We generated hematopoietic-specific poly IC-inducible VPS72-knockout (VPS72^iKO) mice using Mx1-cre mice. Single-cell suspensions of bone marrow (BM) were processed after poly IC induction and analyzed by flow cytometry. Bulk RNA-Seq was performed in sorted myeloid progenitors (Lin^-Sca1^-c-Kit⁺, LK cells). The frequencies of long-term and short-term HSC, lympho-myeloid primed progenitor and megakaryocyte/erythroid progenitor were decreased, whereas common myeloid progenitor and granulocyte/monocyte progenitor were increased in VPS72^iKO mice compared to wild type mice (p≤0.05). Further, VPS72-deficient BM exhibited higher frequencies of neutrophils to the loss of B220⁺ B cells (p≤0.05). Transcriptome analyses showed that VPS72 loss promoted the expression of myeloid related genes (MPO, Myc, Elane, SPi1, Cebpa, Cebpe and Csf3r) and inhibited the expression of lymphoid associated genes (Flt3, Ebf1, Irf4, pax5 and Gfi1b). Overall, VPS72 loss markedly caused perturbations of hematopoietic differentiation compatible with a myeloid bias towards neutrophil production at the expense of B cells, suggesting that VPS72 regulates maintenance or differentiation of HSC. The regulatory pathway of VPS72 offers insight into the equilibrium between normal and pathological hematopoiesis.