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acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Although intensified therapeutic protocols have improved the outcome of T-ALL patients, they coincide with severe short- and long-term side effects. In addition, no salvage therapeutic strategies are available for primary therapy-resistant or relapsed T-ALL, resulting in a dismal outcome for these patients. It highlights the need to identify new targets in T-ALL biology that allow the development of less toxic targeted therapies. PSIP1, a histone mark reader, is a dependency factor in KMT2A-rearranged myeloid leukemia, but is dispensable for normal hematopoiesis, making it an attractive therapeutic target. Nonetheless, rare recurrent inactivating mutations and deletions of PSIP1, suggest that PSIP1 could act as a tumor suppressor in T-ALL. Here, we demonstrate that the loss of Psip1 accelerates T-ALL initiation in mice and we identified a correlation with reduced H3K27me3 binding. Contrastingly, loss of PSIP1 impaired cell proliferation in several human and murine T-ALL cell lines. In these cell lines, PSIP1 loss leads to a significant downregulation of COX20, an assembly factor of the cytochrome c oxidase in the mitochondria, and is associated with a reduction in mitochondrial respiration. Similarly to what was observed for PSIP1, loss of COX20 expression also leads to an impairment of proliferation in these T-ALL cell lines. These data corroborate 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. Overall design: To investigate the role of PSIP1 in both tumor initiation and maintenance, we conducted both in vivo and in vitro experiments in which we modulate PSIP1 expression. We crossed the conditional Psip1 fl/fl model with the spontaneous T-ALL Lck-Cre Pten mouse model and performed survival analysis on these mice. We performed gene expression profiling analysis using data obtained from RNA-seq of tumors derived from the thymus of these mice with or without Psip1 expression. Similarly, we crossed the conditional Psip1 fl/fl model with another spontaneous T-ALL CD2-iCre CD2-Lmo2 mouse model and performed survival analysis on these mice. We performed gene expression profiling analysis using data obtained from RNA-seq of tumors derived from the thymus of these mice with or without Psip1 expression. On the other hand, we performed a knockdown of PSIP1 in a human T-ALL cell line Jurkat by shRNAs. We performed gene expression profiling analysis of RNA-seq data on Jurkat cells for a control hairpin (shCtrl) and 2 different hairpins targetting PSIP1 (shPSIP1 1, shPSIP1 2) 72h after transduction.ENAfalseA dual role for PSIP1/LEDGF in T-cell acute lymphoblastic leukemia [RNA-seq]A dual role for PSIP1/LEDGF in T-cell acute lymphoblastic leukemia [RNA-seq]2025-09-242024-10-29PRJNA1064102GSE25313839485844