The splicing factor RBM25 controls MYC activity in acute myeloid leukemia

Ying Ge,Nikos Sidiropoulos,Frederik Otzen Bagger,Nadia Hashem,Nicolas Rapin,Bo Torben Porse,Sachin Pundhir,Mikkel Bruhn Schuster

doi:10.1038/s41467-018-08076-y

Ying Ge, Nikos Sidiropoulos + Show 6 more

Open Access

https://doi.org/10.1038/s41467-018-08076-y

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Abstract

Cancer sequencing studies have implicated regulators of pre-mRNA splicing as important disease determinants in acute myeloid leukemia (AML), but the underlying mechanisms have remained elusive. We hypothesized that “non-mutated” splicing regulators may also play a role in AML biology and therefore conducted an in vivo shRNA screen in a mouse model of CEBPA mutant AML. This has led to the identification of the splicing regulator RBM25 as a novel tumor suppressor. In multiple human leukemic cell lines, knockdown of RBM25 promotes proliferation and decreases apoptosis. Mechanistically, we show that RBM25 controls the splicing of key genes, including those encoding the apoptotic regulator BCL-X and the MYC inhibitor BIN1. This mechanism is also operative in human AML patients where low RBM25 levels are associated with high MYC activity and poor outcome. Thus, we demonstrate that RBM25 acts as a regulator of MYC activity and sensitizes cells to increased MYC levels.

Highlights

Cancer sequencing studies have implicated regulators of pre-mRNA splicing as important disease determinants in acute myeloid leukemia (AML), but the underlying mechanisms have remained elusive
In order to identify splicing factors that functionally affect AML biology, we conducted an in vivo pooled shRNA screen in the Lp30 AML model
Recent cancer sequencing efforts have uncovered splicing factors as being frequently mutated in hematological malignancies, including myelodysplastic syndrome (MDS) and AML, and premRNA splicing is frequently deregulated in these diseases

Summary

Introduction

Cancer sequencing studies have implicated regulators of pre-mRNA splicing as important disease determinants in acute myeloid leukemia (AML), but the underlying mechanisms have remained elusive. We hypothesized that “non-mutated” splicing regulators may play a role in AML biology and conducted an in vivo shRNA screen in a mouse model of CEBPA mutant AML This has led to the identification of the splicing regulator RBM25 as a novel tumor suppressor. We have conducted an in vivo shRNA screen in the context of the Cebpa mutant AML mouse model aimed at identifying novel tumor suppressors and oncogenes among potential splicing regulators. This led to the identification of RBM25, a relatively uncharacterized RNA binding protein, as a potential tumor suppressor. Our findings provide novel mechanistic insights into the role of RBM25 in AML and a proof-of-concept for the functional importance of splicing deregulation in AML biology in general

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