RNA结合蛋白（RBPs）已成为必不可少的调节基因表达和调控多种癌症特性的调节因子。T细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性的血液恶性肿瘤，来源于正常的T细胞的分化，在胸腺内经历一系列离散的分化步骤。然而，RBPs在T细胞恶性转化过程中的重要性仍然不清楚。系统评估RBPs后，发现RNA解旋酶DHX15是T-ALL的依赖因子，它促进剪接体的解离和大环内含子的释放。在多个小鼠T-ALL模型中的功能分析表明DHX15对肿瘤细胞的生存和白血病发生至关重要。此外，单细胞转录组学揭示，T细胞前体细胞中DHX15的降解阻碍了CD4-CD8-（DN）转变为CD4+CD8+（DP）期间的爆发性增殖。在机械上，DHX15的废除扰乱了RNA剪接，导致SLC7A6和SLC38A5转录本的内含子滞留而降低谷氨酰胺的摄入和mTORC1活性。我们进一步提出了一个DHX15标记调节剂ciclopirox，并展示了杰出的抗T-ALL疗效。总之，我们在这里强调了DHX15对白血病发生的功能贡献，通过调节已知的致癌途径。这些发现还表明，通过靶向剪接体的解离，剪接扰动可能实现可观的抗肿瘤疗效，提出了一种有前途的治疗方法。

RNA-binding proteins (RBPs) have emerged as essential regulators to control gene expression and modulate multiple cancer traits. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy derived from transformation of T-cell progenitors that normally undergo discrete steps of differentiation in the thymus. Yet implications of essential RBPs during T-cell neoplastic transformation remain largely unclear. Systematic evaluation of RBPs identifies RNA helicase DHX15, which facilitates the disassembly of spliceosome and release of lariat introns, as a T-ALL dependency factor. Functional analysis using multiple murine T-ALL models demonstrates the essential importance of DHX15 in tumor cell survival and leukemogenesis. Moreover, single-cell transcriptomics reveals that DHX15 depletion in T-cell progenitors hinders burst proliferation during CD4-CD8-(DN)-to-CD4+CD8+(DP) transition. Mechanistically, abrogation of DHX15 perturbs RNA splicing and leads to diminished levels of SLC7A6 and SLC38A5 transcripts due to intron retention, thereby suppressing glutamine import and mTORC1 activity. We further propose a DHX15 signature modulator drug ciclopirox and demonstrate prominent anti-T-ALL efficacy. Collectively, we here highlight the functional contribution of DHX15 to leukemogenesis through regulation of established oncogenic pathways. These findings also suggest a promising therapeutic approach that splicing perturbation by targeting spliceosome disassembly may achieve considerable anti-tumor efficacy.