A network of RNA-binding proteins maintains splicing and survival in AML.

  • Major finding: A network of RNA-binding proteins maintains splicing and survival in AML.

  • Concept: The RNA-binding protein RBM39 is critical for splicing of essential HOXA9 target gene mRNAs.

  • Impact: Pharmacologic degradation of RBM39 is a potential treatment strategy in spliceosomal-mutant AML.


Recurrent mutations in RNA-binding proteins (RBP) that regulate splicing have been identified in acute myeloid leukemia (AML), and dependencies on several nonmutated RBPs have been discovered. Wang, Lu, Pastore, and colleagues systematically analyzed RBP dependencies in AML by performing a CRISPR/Cas9 RNA binding domain-focused screen against 490 classic RBPs and ultimately identified 8 that were essential for AML survival, were highly expressed in patient samples, and were selectively upregulated in AML. Among the top-scoring candidates was RBM39, whose suppression resulted in growth inhibition and induction of apoptosis in AML cell lines. Mice injected with Rbm39-deleted AML cells exhibited delayed progression, reduced circulating leukemia cells, and prolonged survival, indicating that RBM39 is required for AML survival in vivo. Mass spectrometry analysis revealed an RBM39 interaction network consisting primarily of proteins with roles in the spliceosome complex and ribosome biogenesis, including many other RBPs essential for AML survival. Depletion of RBM39 resulted in several altered splicing events, predominantly repression of cassette exon inclusion and promotion of intron retention. Among the pre-mRNAs most sensitive to RBM39 loss were several HOXA9 targets including BMI1 and GATA2, whose expression is required for leukemogenesis. Pharmacologic inhibition of RBM39 with indisulam (a sulfonamide compound that selectively degrades RBM39) enhanced aberrant splicing and decreased protein levels of HOXA9 targets, leading to cell-cycle arrest and apoptosis in AML cell lines. AML cell lines harboring mutations in splicing factors were significantly more sensitive to indisulam treatment than their wild-type counterparts. In several AML xenograft models, treatment with indisulam elicited strong antileukemic effects, delaying or reducing leukemia burden and prolonging survival. Collectively, these results demonstrate that an RBM39-centered RBP network is critical for survival in AML, particularly those harboring mutations in the spliceosomal machinery, and that targeting RBM39 in this context is a potentially effective therapeutic strategy.

Wang E, Lu SX, Pastore A, Chen X, Imig J, Lee SC, et al. Targeting an RNA-binding protein network in acute myeloid leukemia. Cancer Cell 2019 Feb 21 [Epub ahead of print].

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