CD99 promotes self-renewal in hematopoietic stem cells and leukemia stem cells by regulating protein synthesis
Abstract
Abstract Blood production is sustained by hematopoietic stem cells (HSCs), which are typically the only blood cells capable of long-term self-renewal. HSCs exhibit and depend on low levels of protein synthesis to self-renew. However, the mechanisms by which HSCs regulate protein synthesis to maintain their self-renewal capacity during proliferative stress and leukemogenesis remain unknown. Here we show CD99, a protein upregulated in leukemia stem cells (LSCs) in acute myeloid leukemia (AML), is required for the self-renewal of proliferating HSCs and LSCs. We found that loss of CD99 in HSCs and LSCs leads to increased protein synthesis, and that their self-renewal capacity can be restored by translation inhibition. These data demonstrate a functional role for CD99 in constraining protein synthesis, which may promote the clonal expansion of HSCs and LSCs that leads to AML. Furthermore, these studies demonstrate that similar to HSCs, LSCs depend on maintenance of tightly regulated protein synthesis rates.
Article Details
Authors (14)
Yuanyuan Ji
Yi Huang
Hubei Cancer Hospital Wuhan China
Toby Thomas
Division of Hematology/Oncology, Department of Internal Medicine (T.T., Y.J., B.K., P.C., F.K., A.S., N.P., S.S.C.), UT Southwestern Medical Center, Dallas, TX.
Eda Gozel Kapti
1Division of Hematology/Oncology, Department of Internal Medicine, Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX
Reiko Tachibana
1Division of Hematology/Oncology, Department of Internal Medicine, Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX
Jacob Lark
1Division of Hematology/Oncology, Department of Internal Medicine, Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX
Iryna Berezniuk
Department of Pathology, New York University Grossman School of Medicine
Liang Guo
Department of Chemistry
Mohamed A. E. Ali
Karin Mims
1Division of Hematology/Oncology, Department of Internal Medicine, Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX
Benjamin Kroger
Division of Hematology/Oncology, Department of Internal Medicine (T.T., Y.J., B.K., P.C., F.K., A.S., N.P., S.S.C.), UT Southwestern Medical Center, Dallas, TX.
Wenhuo Hu
Department of Pathology, Center of Excellence for Leukemia Studies, St. Jude Children’s Research Hospital, Memphis, TN (W.H.).
Christopher Y. Park
Perlmutter Cancer Center, New York University Langone Health
Stephen S. Chung