Abstract
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Current intensified therapeutic protocols coincide with severe side effects, and no salvage therapy is available for primary therapy-resistant or relapsed patients. This highlights the need to identify new therapeutic targets in T-ALL. PSIP1, dispensable for normal hematopoiesis, is a dependency factor in KMT2A-rearranged myeloid leukemia. Nonetheless, loss-of-function mutations suggest a tumor suppressor role for PSIP1 in T-ALL. Here, we demonstrate that the loss of Psip1 accelerates T-ALL initiation in mice which we correlated with reduced H3K27me3 binding. Contrastingly, loss of PSIP1 impaired cell proliferation in several T-ALL cell lines. In cell lines, PSIP1 down-regulation leads to a reduction of COX20, an assembly factor of the cytochrome c oxidase in the mitochondria, and to a reduction in mitochondrial respiration. This indicates that PSIP1 can exert a dual role in the context of T-ALL, either as a tumor suppressor gene during tumor initiation or as a dependency factor in tumor maintenance.