PI3-kinase deletion promotes myelodysplasia by dysregulating autophagy in hematopoietic stem cells

Kristina Ames, Imit Kaur, Yang Shi, Meng M. Tong, Taneisha Sinclair, Shayda Hemmati, Shira G. Glushakow-Smith, Ellen Tein, Lindsay Gurska, Ulrich Steidl, Robert Dubin, Jidong Shan, Cristina Montagna, Kith Pradhan, Amit Verma, Kira Gritsman

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Myelodysplastic syndrome (MDS) is a clonal malignancy arising in hematopoietic stem cells (HSCs). The mechanisms of MDS initiation in HSCs are still poorly understood. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is frequently activated in acute myeloid leukemia, but in MDS, PI3K/AKT is often down-regulated. To determine whether PI3K down-regulation can perturb HSC function, we generated a triple knockout (TKO) mouse model with Pik3ca, Pik3cb, and Pik3cd deletion in hematopoietic cells. Unexpectedly, PI3K deficiency caused cytopenias, decreased survival, and multilineage dysplasia with chromosomal abnormalities, consistent with MDS initiation. TKO HSCs exhibit impaired autophagy, and pharmacologic autophagy induction improved HSC differentiation. Using intracellular LC3 and P62 flow cytometry and transmission electron microscopy, we also observed abnormal autophagic degradation in patient MDS HSCs. Therefore, we have uncovered an important protective role for PI3K in maintaining autophagic flux in HSCs to preserve the balance between self-renewal and differentiation and to prevent MDS initiation.

Original languageEnglish (US)
Article numbereade8222
JournalScience Advances
Volume9
Issue number8
DOIs
StatePublished - Feb 2023

ASJC Scopus subject areas

  • General

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