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

Biochem Biophys Res Commun. 2022 Sep 17:621:74-79. doi: 10.1016/j.bbrc.2022.06.089. Epub 2022 Jun 30.

Abstract

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.

Keywords: Nucleotide metabolism; RHEB; T-ALL; mTOR; mTORC1.

MeSH terms

  • Animals
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / genetics
  • Ras Homolog Enriched in Brain Protein* / genetics
  • Ras Homolog Enriched in Brain Protein* / metabolism
  • Signal Transduction
  • T-Lymphocytes / metabolism
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • RHEB protein, human
  • Ras Homolog Enriched in Brain Protein
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases