The splicing factor RBM25 controls MYC activity in acute myeloid leukemia

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

doi:10.1038/s41467-018-08076-y

The splicing factor RBM25 controls MYC activity in acute myeloid leukemia

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

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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.

Original language	English
Article number	172
Journal	Nature Communications
Volume	10
Issue number	1
Number of pages	14
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-018-08076-y
Publication status	Published - 1 Dec 2019

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The splicing factor RBM25 controls MYC activity in acute myeloid leukemiaFinal published version, 1.73 MBLicence: CC BY

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title = "The splicing factor RBM25 controls MYC activity in acute myeloid leukemia",

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.",

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T1 - The splicing factor RBM25 controls MYC activity in acute myeloid leukemia

AU - Ge, Ying

AU - Schuster, Mikkel Bruhn

AU - Pundhir, Sachin

AU - Rapin, Nicolas

AU - Bagger, Frederik Otzen

AU - Sidiropoulos, Nikos

AU - Hashem, Nadia

AU - Porse, Bo Torben

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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The splicing factor RBM25 controls MYC activity in acute myeloid leukemia

Abstract

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