| Autor: |
Loc Thi Pham, Hui Peng, Masaya Ueno, Susumu Kohno, Atuso Kasada, Kazuyoshi Hosomichi, Takehiro Sato, Kenta Kurayoshi, Masahiko Kobayashi, Yuko Tadokoro, Atsuko Kasahara, Mahmoud I. Shoulkamy, Bo Xiao, Paul F. Worley, Chiaki Takahashi, Atsushi Tajima, Atsushi Hirao |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Biochemical and Biophysical Research Communications. 621:74-79 |
| ISSN: |
0006-291X |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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