The RBM39 degrader indisulam inhibits acute megakaryoblastic leukemia by altering the alternative splicing of ZMYND8

Area of Science:

• Hematology
• Molecular Biology
• Oncology

Background:

• Acute megakaryoblastic leukemia (AMKL) is a rare hematological malignancy.
• Alternative splicing (AS) is implicated in cancer progression, highlighting splicing factors as therapeutic targets.

Purpose of the Study:

• To investigate the efficacy of indisulam, a molecular glue degrader targeting RNA binding motif protein 39 (RBM39), in AMKL models.

Main Methods:

• Analysis of public drug sensitivity data for AMKL cell lines.
• Assessment of indisulam's effects on RBM39 depletion, cell cycle arrest, and apoptosis.
• Evaluation of indisulam in an AMKL mouse model.
• Integration of transcriptomic and proteomic analyses to elucidate molecular mechanisms.
• Investigation of DDB1- and Cul4- Associated Factor 15 (DCAF15) dependency.

Main Results:

• AMKL cell lines demonstrated high sensitivity to indisulam.
• Indisulam treatment led to RBM39 depletion, inducing cell cycle arrest and apoptosis in AMKL cells.
• Indisulam reduced leukemic burden and prolonged survival in an AMKL mouse model.
• Indisulam-induced RBM39 degradation resulted in alternative splicing of ZMYND8, a regulator of AMKL cell growth.
• DCAF15 expression was essential for indisulam's efficacy, as DCAF15 knockout abrogated indisulam-induced RBM39 degradation and ZMYND8 mis-splicing.

Conclusions:

• Indisulam is a potential therapeutic agent for AMKL.
• The RBM39-mediated splicing of ZMYND8 is crucial for AMKL development.