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Ref Type Journal Article
PMID (30799057)
Authors Wang E, Lu SX, Pastore A, Chen X, Imig J, Chun-Wei Lee S, Hockemeyer K, Ghebrechristos YE, Yoshimi A, Inoue D, Ki M, Cho H, Bitner L, Kloetgen A, Lin KT, Uehara T, Owa T, Tibes R, Krainer AR, Abdel-Wahab O, Aifantis I
Title Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia.
Journal Cancer cell
Vol 35
Issue 3
Date 2019 03 18
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
U2AF1 S34F acute myeloid leukemia sensitive Indisulam Preclinical - Cell culture Actionable In a preclinical study, an acute myeloid leukemia cell line engineered to express U2AF1 S34F from the endogenous locus demonstrated increased sensitivity to Indisulam (E7070) induced growth inhibition compared to parental cells in culture (PMID: 30799057). 30799057
U2AF1 S34F acute myeloid leukemia sensitive E7820 Preclinical - Cell culture Actionable In a preclinical study, an acute myeloid leukemia cell line engineered to express U2AF1 S34F from the endogenous locus demonstrated increased sensitivity to E7820 induced growth inhibition compared to parental cells in culture (PMID: 30799057). 30799057
SF3B1 K666N B-cell acute lymphoblastic leukemia sensitive Indisulam Preclinical - Cell culture Actionable In a preclinical study, a B-cell acute lymphoblastic leukemia cell line engineered to express SF3B1 K666N from the endogenous locus demonstrated increased sensitivity to Indisulam (E7070) induced growth inhibition compared to parental cells in culture (PMID: 30799057). 30799057
SF3B1 K700E B-cell acute lymphoblastic leukemia sensitive Indisulam Preclinical - Cell culture Actionable In a preclinical study, a B-cell acute lymphoblastic leukemia cell line engineered to express SF3B1 K700E from the endogenous locus demonstrated increased sensitivity to Indisulam (E7070) induced growth inhibition compared to parental cells in culture (PMID: 30799057). 30799057
SF3B1 H662Q B-cell acute lymphoblastic leukemia sensitive E7820 Preclinical - Cell culture Actionable In a preclinical study, a B-cell acute lymphoblastic leukemia cell line engineered to express SF3B1 H662Q from the endogenous locus demonstrated increased sensitivity to E7820 induced growth inhibition compared to parental cells in culture (PMID: 30799057). 30799057
SF3B1 K700E acute myeloid leukemia sensitive Indisulam Preclinical - Cell culture Actionable In a preclinical study, an acute myeloid leukemia cell line engineered to express SF3B1 K700E from the endogenous locus demonstrated increased sensitivity to Indisulam (E7070) induced growth inhibition compared to parental cells in culture (PMID: 30799057). 30799057
SF3B1 K700E B-cell acute lymphoblastic leukemia sensitive E7820 Preclinical - Cell culture Actionable In a preclinical study, a B-cell acute lymphoblastic leukemia cell line engineered to express SF3B1 K700E from the endogenous locus demonstrated increased sensitivity to E7820 induced growth inhibition compared to parental cells in culture (PMID: 30799057). 30799057
SRSF2 P95H acute myeloid leukemia sensitive E7820 Preclinical - Cell culture Actionable In a preclinical study, an acute myeloid leukemia cell line engineered to express SRSF2 P95H from the endogenous locus demonstrated increased sensitivity to E7820 induced growth inhibition compared to parental cells in culture (PMID: 30799057). 30799057
SF3B1 H662Q B-cell acute lymphoblastic leukemia sensitive Indisulam Preclinical - Cell culture Actionable In a preclinical study, a B-cell acute lymphoblastic leukemia cell line engineered to express SF3B1 H662Q from the endogenous locus demonstrated increased sensitivity to Indisulam (E7070) induced growth inhibition compared to parental cells in culture (PMID: 30799057). 30799057
SF3B1 K666N B-cell acute lymphoblastic leukemia sensitive E7820 Preclinical - Cell culture Actionable In a preclinical study, a B-cell acute lymphoblastic leukemia cell line engineered to express SF3B1 K666N from the endogenous locus demonstrated increased sensitivity to E7820 induced growth inhibition compared to parental cells in culture (PMID: 30799057). 30799057
SRSF2 P95H acute myeloid leukemia sensitive Indisulam Preclinical - Cell culture Actionable In a preclinical study, an acute myeloid leukemia cell line engineered to express SRSF2 P95H from the endogenous locus demonstrated increased sensitivity to Indisulam (E7070) induced growth inhibition compared to parental cells in culture (PMID: 30799057). 30799057
SF3B1 K666N acute myeloid leukemia sensitive Indisulam Preclinical - Cell culture Actionable In a preclinical study, an acute myeloid leukemia cell line engineered to express SF3B1 K666N from the endogenous locus demonstrated increased sensitivity to Indisulam (E7070) induced growth inhibition compared to parental cells in culture (PMID: 30799057). 30799057
SF3B1 K700E acute myeloid leukemia predicted - sensitive E7820 Preclinical - Cell culture Actionable In a preclinical study, an acute myeloid leukemia cell line engineered to express SF3B1 K700E from the endogenous locus demonstrated increased sensitivity to E7820 induced growth inhibition compared to parental cells in culture (PMID: 30799057). 30799057
SF3B1 K666N acute myeloid leukemia sensitive E7820 Preclinical - Cell culture Actionable In a preclinical study, an acute myeloid leukemia cell line engineered to express SF3B1 K666N from the endogenous locus demonstrated increased sensitivity to E7820 induced growth inhibition compared to parental cells in culture (PMID: 30799057). 30799057