The splicing factor RBM25 controls MYC activity in acute myeloid leukemia

• Published in: Nature communications 2019-01, Vol.10 (1), p.172-172, Article 172
• Main Authors: Ge, Ying, Schuster, Mikkel Bruhn, Pundhir, Sachin, Rapin, Nicolas, Bagger, Frederik Otzen, Sidiropoulos, Nikos, Hashem, Nadia, Porse, Bo Torben
• Format: Article
• Language: English
• Subjects: 13/106; 13/2; 13/31; 13/89; 45/91; 49/39; 631/337/1645/1792; 631/67/1990/283; 631/80/304; 64/60; Acute myeloid leukemia; Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis; Bcl-x protein; Cancer; Cell Line, Tumor; Female; Gene Expression Regulation, Leukemic; Gene sequencing; Humanities and Social Sciences; Humans; Leukemia; Leukemia, Experimental - metabolism; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - mortality; Mice; mRNA; multidisciplinary; Myc protein; Myeloid leukemia; Nerve Tissue Proteins - metabolism; Proto-Oncogene Proteins c-myc - metabolism; Regulators; RNA Recognition Motif Proteins - metabolism; RNA Splicing; RNA Splicing Factors - metabolism; RNA-Binding Proteins - metabolism; Science; Science (multidisciplinary); Splicing; Splicing factors; Tumor suppressor genes; Tumor Suppressor Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-08076-y

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. Splicing factors are often mutated in hematological malignancies. Here, the authors perform an in vivo shRNA screen in a CEBPA mutant AML mouse model and identify that RBM25 controls the splicing of pre-mRNAs encoding BCL-X and BIN1 to exert its tumour suppressor activities in AML.