期刊
CANCER CELL
卷 35, 期 3, 页码 369-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2019.01.010
关键词
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资金
- National Institutes of Health/National Cancer Institute [P30CA016087-30]
- NIH T32 Genome Integrity grant
- Conquer Cancer Foundation
- ASCOYoung Investigator Award
- Aplastic Anemia & Myelodysplastic Syndrome International Foundation research award
- AACR Lymphoma Research Fellowship
- US National Institutes of Health [R01 HL128239, 1R01 CA228135, 1R01 CA216421, 1R01CA194923, 1R01CA169784, 5RO1CA173636]
- Pershing Square Sohn Cancer Research Alliance
- Evans MDS Foundation
- Druckenmiller Center for Lung Cancer Research at MSK
- Department of Defense Bone Marrow Failure Research Program [BM150092, W81XWH-12-1-0041]
- Starr Cancer Consortium [I8-A8-075]
- Taub Foundation
- Leukemia & Lymphoma Society [6499-17]
- Alex's Lemonade Stand Foundation for Childhood Cancer
- St. Baldrick's Cancer Research Foundation
- New York State Department of Health [CO030132, C32587GG, C32563GG]
RNA-binding proteins (RBPs) are essential modulators of transcription and translation frequently dysregulated in cancer. We systematically interrogated RBP dependencies in human cancers using a comprehensive CRISPR/Cas9 domain-focused screen targeting RNA-binding domains of 490 classical RBPs. This uncovered a network of physically interacting RBPs upregulated in acute myeloid leukemia (AML) and crucial for maintaining RNA splicing and AML survival. Genetic or pharmacologic targeting of one key member of this network, RBM39, repressed cassette exon inclusion and promoted intron retention within mRNAs encoding HOXA9 targets as well as in other RBPs preferentially required in AML. The effects of RBM39 loss on splicing further resulted in preferential lethality of spliceosomal mutant AML, providing a strategy for treatment of AML bearing RBP splicing mutations.
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