Abstract
Depletion of the RNA-binding protein (RBP) SYNCRIP promotes leukemic cell differentiation and apoptosis.
Major finding: Depletion of the RNA-binding protein (RBP) SYNCRIP promotes leukemic cell differentiation and apoptosis.
Mechanism: SYNCRIP and MSI2 regulate mRNAs targeted by MLL-AF9 and involved in the leukemic stem cell program.
Impact: RBPs including SYNCRIP may be potential therapeutic targets in patients with leukemia.
RNA-binding proteins (RBP) control post-transcriptional regulation to regulate protein abundance and diversity, which can influence cell fate decisions. Mutations in or aberrant expression of RBPs have been linked to hematologic disease and leukemia; however, most RBPs have not been functionally characterized, and their role in leukemia is unclear. Vu and colleagues performed an in vivo shRNA screen in mice with MLL-AF9–driven leukemia to identify RBPs that promote leukemic progression. One of the top hits was Syncrip, which has three tandem RNA recognition motifs and is involved in RNA processing. SYNCRIP interacts with MSI2, an RBP associated with aggressive leukemia that is required for self-renewal of leukemic stem cells (LSC). In MLL-AF9 leukemia cells, SYNCRIP depletion promoted rapid myeloid differentiation and subsequent apoptosis. Further, SYNCRIP depletion extended survival in mice with MLL-AF9–driven leukemia. Conversely, SYNCRIP overexpression promoted leukemia cell proliferation, altogether suggesting that SYNCRIP promotes leukemia cell growth and survival and maintains an undifferentiated state. In vivo, CRISPR/Cas9-mediated Syncrip deletion delayed leukemogenesis, but did not disrupt normal hematopoiesis. SYNCRIP was highly expressed in patients with acute myeloid leukemia (AML) driven by various oncogenic genetic alterations. RNA sequencing revealed that SYNCRIP depletion downregulated MLL-AF9 target genes and resulted in loss of the LSC gene expression program. Moreover, SYNCRIP bound to MSI2 to coregulate translation of shared mRNA targets including Hoxa9. Expression of HOXA9 was able to partially rescue the survival defects in SYNCRIP-depleted cells, suggesting that SYNCRIP promotes myeloid leukemia in part by regulating HOXA9 expression. The finding that SYNCRIP and MSI2 regulate mRNAs targeted by MLL-AF9 and mRNAs involved in self-renewal suggests that RBPs have essential roles in leukemia and may be potential therapeutic targets.
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