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 - 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 -