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.