The aryl sulfonamide indisulam inhibits acute megakaryoblastic leukemia (AMKL) by altering the alternative splicing of the transcription factor ZMYND8

ABSTRACT: Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia with clinical heterogeneity. The poor prognosis of AMKL means that new therapies need to be developed to treat this disease. Studies have shown that the dysregulation of alternative splicing is associated with the occurrence and development of AMKL and the increase of chemotherapy resistance. indisulam, as a synthetic aryl sulfonamide, can effectively treat solid tumors by targeting the splicing factor RBM39. However, the effects of indisulam on AMKL and the underlying molecular mechanisms remain to be thoroughly investigated. We first screened AMKL for indisulam susceptibility in a public drug-susceptibility database. The results showed that AMKL was more sensitive to insulin than other tumor types. We then treated human AMKL cell lines (CMK, MEG01 and M07e) with indisulam to evaluate its efficacy and investigate its molecular targets. The results suggest that indisulam induces RBM39 degradation and inhibits tumor growth in a dose-dependent manner. RNA-seq and proteomic analyses revealed that indisulam selectively degraded RBM39 and resulted in mis-splicing of the transcription factor ZMYND8, which maintains AML survival and proliferation. We knocked down ZMYND8 and confirmed the critical role of ZMYND8 in maintaining AMKL survival and proliferation. In addition, we verified that the anti-tumor effect of indisulam on AMKL was DCAF15 dependent. By targeting DCAF15 using CRISPR/Cas9 system, we confirmed the DCAF15-dependent effect of indisulam in both in vivo and in vitro models. Taken together, our study suggests that indisulam has promising therapeutic potential for AMKL by specifically targeting the splicing factor RBM39 and is dependent on the expression of DCAF15. In addition, our study identified ZMYND8 as a novel downstream regulator of RBM39 and the RBM39-ZMYND8 axis is important for AMKL survival and proliferation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266925 | GEO | 2025/04/23

REPOSITORIES: GEO