Identification of AK4 and RHOC as potential oncogenes addicted by adult T cell leukemia.

in Proceedings of the National Academy of Sciences of the United States of America by Benquan Liu, Jun-Ichirou Yasunaga, Yi Liang, Ruoning Zhou, Sikai Yang, Xiaoyi Yuan, Jie Liu, Xiaorui Zuo, Michi Miura, Yusuke Higuchi, Takashi Matsumoto, Kosuke Toyoda, Masao Matsuoka, Guangyong Ma

TLDR

  • The study identified AK4 and RHOC oncogenes and the oncometabolite sphingomyelin as targetable vulnerabilities of ATL.
  • Atl showed sensitivity to sphingomyelin inhibition and AK4 or RHOC depletion.
  • The findings have implications for the development of targeted therapeutics for ATL.

Abstract

Adult T cell leukemia (ATL) is a highly aggressive T cell malignancy characterized by human T cell leukemia virus type 1 (HTLV-1) infection. ATL has a very poor prognosis and lacks satisfactory treatments; therefore, it is critical to identify potential targets in ATL cells in order to develop effective targeted therapeutics. Here, we report the identification of two oncogenes, AK4 and RHOC, as target genes of miR-455-3p, a tumor-suppressive microRNA in ATL patients. Importantly, AK4 and RHOC are highly expressed in ATL and exhibit oncogenic potentials in vitro and in vivo. Interestingly, transcriptome and metabolome analyses reveal a functional overlap of AK4 and RHOC, including activating oncogenic pathways such as Myc targets and deregulating lipid metabolism such as enhancing the production of sphingomyelin, a tumor-promoting lipid. In particular, compared to other types of T cell malignancy such as T cell acute lymphoblastic leukemia (T-ALL) and cutaneous T cell lymphoma (CTCL), ATL is sensitive to sphingomyelin inhibition and AK4 or RHOC depletion. Altogether, we report a distinct dependency of ATL on AK4 and RHOC oncogenes and an oncometabolite sphingomyelin, which together represent targetable vulnerabilities of ATL that could be exploited for developing effective therapeutics.

Overview

  • The study focused on identifying potential targets in Adult T cell leukemia (ATL) cells to develop effective targeted therapeutics.
  • The researchers used miR-455-3p, a tumor-suppressive microRNA, to identify target genes in ATL cells and found two oncogenes, AK4 and RHOC.
  • The primary objective of the study was to identify targetable vulnerabilities of ATL that could be exploited for developing effective therapeutics.

Comparative Analysis & Findings

  • The study found that AK4 and RHOC are highly expressed in ATL and exhibit oncogenic potentials in vitro and in vivo.
  • Transcriptome and metabolome analyses revealed a functional overlap of AK4 and RHOC, including activating oncogenic pathways and deregulating lipid metabolism.
  • Atl showed sensitivity to sphingomyelin inhibition and AK4 or RHOC depletion, whereas other types of T cell malignancy, such as T-ALL and CTCL, did not.

Implications and Future Directions

  • The findings suggest that AK4 and RHOC oncogenes and the oncometabolite sphingomyelin represent targetable vulnerabilities of ATL.
  • Future studies could explore the potential of inhibiting sphingomyelin or depleting AK4 or RHOC as a therapeutic approach for ATL.
  • The study highlights the importance of understanding the genetic and metabolic mechanisms underlying ATL to develop effective treatments.
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