TY - JOUR
T1 - Loss of Atg2b and Gskip Impairs the Maintenance of the Hematopoietic Stem Cell Pool Size
AU - Sakai, Shun Suke
AU - Hasegawa, Atsushi
AU - Ishimura, Ryosuke
AU - Tamura, Naoki
AU - Kageyama, Shun
AU - Komatsu-Hirota, Satoko
AU - Abe, Manabu
AU - Ling, Yiwei
AU - Okuda, Shujiro
AU - Funayama, Manabu
AU - Kikkawa, Mika
AU - Miura, Yoshiki
AU - Sakimura, Kenji
AU - Narita, Ichiei
AU - Waguri, Satoshi
AU - Shimizu, Ritsuko
AU - Komatsu, Masaaki
N1 - Funding Information:
M.K. is supported by a Grant-in-Aid for Scientific Research on Innovative Areas (grant 19H05706), by a Grant-in-Aid for Scientific Research (A) (grant 21H004771), by the Japan Society for the Promotion of Science (an A3 foresight program), and by the Takeda Science Foundation (to M.K.). This work was supported by JSPS KAKENHI grant JP 16H06276 (AdAMS).
Publisher Copyright:
© 2022 American Society for Microbiology. All rights reserved.
PY - 2022/1
Y1 - 2022/1
N2 - A germ line copy number duplication of chromosome 14q32, which contains ATG2B and GSKIP, was identified in families with myeloproliferative neoplasm (MPN). Here, we show that mice lacking both Atg2b and Gskip, but not either alone, exhibited decreased hematopoiesis, resulting in death in utero accompanied by anemia. In marked contrast to MPN patients with duplication of ATG2B and GSKIP, the number of hematopoietic stem cells (HSCs), in particular long-term HSCs, in double-knockout fetal livers was significantly decreased due to increased cell death. Although the remaining HSCs still had the ability to differentiate into hematopoietic progenitor cells, the differentiation efficiency was quite low. Remarkably, mice with knockout of Atg2b or Gskip alone did not show any hematopoietic abnormality. Mechanistically, while loss of both genes had no effect on autophagy, it increased the expression of genes encoding enzymes involved in oxidative phosphorylation. Taken together, our results indicate that Atg2b and Gskip play a synergistic effect in maintaining the pool size of HSCs.
AB - A germ line copy number duplication of chromosome 14q32, which contains ATG2B and GSKIP, was identified in families with myeloproliferative neoplasm (MPN). Here, we show that mice lacking both Atg2b and Gskip, but not either alone, exhibited decreased hematopoiesis, resulting in death in utero accompanied by anemia. In marked contrast to MPN patients with duplication of ATG2B and GSKIP, the number of hematopoietic stem cells (HSCs), in particular long-term HSCs, in double-knockout fetal livers was significantly decreased due to increased cell death. Although the remaining HSCs still had the ability to differentiate into hematopoietic progenitor cells, the differentiation efficiency was quite low. Remarkably, mice with knockout of Atg2b or Gskip alone did not show any hematopoietic abnormality. Mechanistically, while loss of both genes had no effect on autophagy, it increased the expression of genes encoding enzymes involved in oxidative phosphorylation. Taken together, our results indicate that Atg2b and Gskip play a synergistic effect in maintaining the pool size of HSCs.
KW - ATG2B
KW - GSKIP
KW - autophagy
KW - hematopoiesis
KW - hematopoietic stem cell
KW - myeloproliferative neoplasm
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U2 - 10.1128/MCB.00024-21
DO - 10.1128/MCB.00024-21
M3 - Article
C2 - 34748402
AN - SCOPUS:85123814141
SN - 0270-7306
VL - 42
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 1
M1 - e00024-21
ER -