RHEB is a potential therapeutic target in T cell acute lymphoblastic leukemia

Pham，Loc Thi1; Peng，Hui1; Ueno，Masaya1,2; Kohno，Susumu3; Kasada，Atuso1; Hosomichi，Kazuyoshi4; Sato，Takehiro4; Kurayoshi，Kenta1; Kobayashi，Masahiko1; Tadokoro，Yuko1,2; Kasahara，Atsuko1,2,5; Shoulkamy，Mahmoud I.1,2,6; Xiao，Bo7; Worley，Paul F.8; Takahashi，Chiaki3; Tajima，Atsushi4; Hirao，Atsushi1,2

2022-09-17

10.1016/j.bbrc.2022.06.089

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   Impact Factor & Quartile

0006-291X

1090-2104

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of immature T lymphocytes. Although various therapeutic approaches have been developed, refractoriness of chemotherapy and relapse cause a poor prognosis of the disease and further therapeutic strategies are required. Here, we report that Ras homolog enriched in brain (RHEB), a critical regulator of mTOR complex 1 activity, is a potential target for T-ALL therapy. In this study, we established an sgRNA library that comprehensively targeted mTOR upstream and downstream pathways, including autophagy. CRISPR/Cas9 dropout screening revealed critical roles of mTOR-related molecules in T-ALL cell survival. Among the regulators, we focused on RHEB because we previously found that it is dispensable for normal hematopoiesis in mice. Transcriptome and metabolic analyses revealed that RHEB deficiency suppressed de novo nucleotide biosynthesis, leading to human T-ALL cell death. Importantly, RHEB deficiency suppressed tumor growth in both mouse and xenograft models. Our data provide a potential strategy for efficient therapy of T-ALL by RHEB-specific inhibition.

mTOR mTORC1 Nucleotide metabolism RHEB T-ALL

SCI

English

Others

Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan[17K09919] ; MEXT[19H01033] ; Japan Agency for Medical Research and Development (AMED)[21cm0106104h0006]

Biochemistry & Molecular Biology ; Biophysics

Biochemistry & Molecular Biology ; Biophysics

WOS:000878141800012

ACADEMIC PRESS INC ELSEVIER SCIENCE

BIOLOGY & BIOCHEMISTRY

2-s2.0-85133810952

Scopus

1.Division of Molecular Genetics,Cancer and Stem Cell Research Program,Cancer Research Institute,Kanazawa University,Kanazawa,Kakuma-machi,920-1192,Japan
2.WPI Nano Life Science Institute (WPI-Nano LSI),Kanazawa University,Kanazawa,Kakuma-machi,920-1192,Japan
3.Division of Oncology and Molecular Biology,Cancer Research Institute,Kanazawa University,Kanazawa,Kakuma-machi,920-1192,Japan
4.Department of Bioinformatics and Genomics,Graduate School of Advanced Preventive Medical Sciences,Kanazawa University,Kanazawa,13-1 Takara-machi,920-8640,Japan
5.Institute for Frontier Science Initiative,Kanazawa University,Kanazawa,Kakuma-machi,920-1192,Japan
6.Zoology Department,Faculty of Science,Minia University,El-Minia,61519,Egypt
7.Department of Biology,School of Life Sciences,Brain Research Center,Southern University of Science and Technology,Shenzhen Key Laboratory of Gene Regulation and Systems Biology,Shenzhen,518055,China
8.The Solomon H. Snyder Department of Neuroscience,Johns Hopkins University School of Medicine,Baltimore,21205,United States

Pham，Loc Thi,Peng，Hui,Ueno，Masaya,et al. RHEB is a potential therapeutic target in T cell acute lymphoblastic leukemia[J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,2022,621:74-79.

Pham，Loc Thi.,Peng，Hui.,Ueno，Masaya.,Kohno，Susumu.,Kasada，Atuso.,...&Hirao，Atsushi.(2022).RHEB is a potential therapeutic target in T cell acute lymphoblastic leukemia.BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,621,74-79.

Pham，Loc Thi,et al."RHEB is a potential therapeutic target in T cell acute lymphoblastic leukemia".BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 621(2022):74-79.