TY - JOUR
T1 - PI3-kinase deletion promotes myelodysplasia by dysregulating autophagy in hematopoietic stem cells
AU - Ames, Kristina
AU - Kaur, Imit
AU - Shi, Yang
AU - Tong, Meng M.
AU - Sinclair, Taneisha
AU - Hemmati, Shayda
AU - Glushakow-Smith, Shira G.
AU - Tein, Ellen
AU - Gurska, Lindsay
AU - Steidl, Ulrich
AU - Dubin, Robert
AU - Shan, Jidong
AU - Montagna, Cristina
AU - Pradhan, Kith
AU - Verma, Amit
AU - Gritsman, Kira
N1 - Funding Information:
This work was supported by National Institutes of Health grants R01CA196973 (to K.G.), R56DK130895-01 (to K.G.), R01DK130895-01 (to K.G.), and K08CA149208 (to K.G.); startup funds from AECOM and Albert Einstein Cancer Center (AECC) (to K.G.); the American Society of Hematology (to K.G.); the NHLBI/NIH Ruth L. Kirschstein National Research Service Award F32HL146119 (to K.A.); the IRACDA/BETTR training Institutional Research and Academic Career Development Award 2K12GH102779-07A1 (to K.A.); the Training Program in Cellular and Molecular Biology and Genetics at AECOM #5T32GM007491-44 (to L.G.); and the National Cancer Institute of NIH fellowship F31CA247172 (to L.G.). S.H. was partially supported by The Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund through New York State Department of Health Contract C30292GG, as well as by AECC Support Grant of the NIH under award number P30CA013330. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported through Dr. Daqian Sun from the Stem Cell Isolation and Xenotransplantation Core Facility (NYSTEM grant #C029154) of the Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine. For flow cytometry, this work used the analyzers Cytek Aurora Multiparameter Flow Cytometer and BD LSR-II with the help from J. Zhang and A. Fnu. The Cytek Aurora Multiparameter Flow Cytometer was purchased with funding from the NIH SIG grant #1S10OD026833-01. This work used a Leica SP8 Laser Scanning Confocal Microscope, with help from V. DesMarais, H. Guzik and A. Briceno of the Analytical Imaging Facility at AECOM. The microscope was purchased with funding from an NIH SIG grant #1S10OD023591-01. Electron imaging was done with the help of F. Macaluso, L. G. Cummins, and X. Nishku.
Publisher Copyright:
Copyright © 2023 The Authors, some rights reserved.
PY - 2023/2
Y1 - 2023/2
N2 - 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.
AB - 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.
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U2 - 10.1126/sciadv.ade8222
DO - 10.1126/sciadv.ade8222
M3 - Article
C2 - 36812307
AN - SCOPUS:85148773055
SN - 2375-2548
VL - 9
JO - Science advances
JF - Science advances
IS - 8
M1 - eade8222
ER -