Reference Detail

Ref Type Journal Article
PMID (30333627)
Authors Tyner JW, Tognon CE, Bottomly D, Wilmot B, Kurtz SE, Savage SL, Long N, Schultz AR, Traer E, Abel M, Agarwal A, Blucher A, Borate U, Bryant J, Burke R, Carlos A, Carpenter R, Carroll J, Chang BH, Coblentz C, d'Almeida A, Cook R, Danilov A, Dao KT, Degnin M, Devine D, Dibb J, Edwards DK, Eide CA, English I, Glover J, Henson R, Ho H, Jemal A, Johnson K, Johnson R, Junio B, Kaempf A, Leonard J, Lin C, Liu SQ, Lo P, Loriaux MM, Luty S, Macey T, MacManiman J, Martinez J, Mori M, Nelson D, Nichols C, Peters J, Ramsdill J, Rofelty A, Schuff R, Searles R, Segerdell E, Smith RL, Spurgeon SE, Sweeney T, Thapa A, Visser C, Wagner J, Watanabe-Smith K, Werth K, Wolf J, White L, Yates A, Zhang H, Cogle CR, Collins RH, Connolly DC, Deininger MW, Drusbosky L, Hourigan CS, Jordan CT, Kropf P, Lin TL, Martinez ME, Medeiros BC, Pallapati RR, Pollyea DA, Swords RT, Watts JM, Weir SJ, Wiest DL, Winters RM, McWeeney SK, Druker BJ
Title Functional genomic landscape of acute myeloid leukaemia.
Journal Nature
Vol 562
Issue 7728
Date 2018 10
URL
Abstract Text The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset-accessible through the Beat AML data viewer (Vizome)-that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.

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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
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
BCOR mut RUNX1 mut acute myeloid leukemia predicted - sensitive Tofacitinib Preclinical - Patient cell culture Actionable In a preclinical study, co-occurrence of BCOR and RUNX1 mutations correlated with sensitivity to Xeljanz (tofacitinib) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
FLT3 exon 14 ins acute myeloid leukemia predicted - sensitive Sorafenib Preclinical - Patient cell culture Actionable In a preclinical study, FLT3-ITD mutations correlated with sensitivity to Nexavar (sorafenib) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
BCOR mut RUNX1 mut acute myeloid leukemia predicted - sensitive Ruxolitinib Preclinical - Patient cell culture Actionable In a preclinical study, co-occurrence of BCOR and RUNX1 mutations correlated with sensitivity to Jakafi (ruxolitinib) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
DNMT3A mut NPM1 mut acute myeloid leukemia predicted - sensitive Ibrutinib Preclinical - Patient cell culture Actionable In a preclinical study, co-occurrence of DNMT3A and NPM1 mutations correlated with sensitivity to Imbruvica (ibrutinib) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
FLT3 exon 14 ins NPM1 mutant acute myeloid leukemia predicted - sensitive Sunitinib Preclinical - Patient cell culture Actionable In a preclinical study, co-occurrence of FLT3-ITD and NPM1 mutations correlated with sensitivity to Sutent (sunitinib) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
FLT3 exon 14 ins NPM1 mutant acute myeloid leukemia predicted - sensitive Ibrutinib Preclinical - Patient cell culture Actionable In a preclinical study, co-occurrence of FLT3-ITD and NPM1 mutations correlated with sensitivity to Imbruvica (ibrutinib) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
FLT3 exon 14 ins acute myeloid leukemia predicted - sensitive Entospletinib Preclinical - Patient cell culture Actionable In a preclinical study, FLT3-ITD mutations correlated with sensitivity to Entospletinib in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
FLT3 exon 14 ins NPM1 mutant acute myeloid leukemia predicted - sensitive Entospletinib Preclinical - Patient cell culture Actionable In a preclinical study, co-occurrence of FLT3-ITD and NPM1 mutations correlated with sensitivity to Entospletinib in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
FLT3 exon 14 ins acute myeloid leukemia predicted - sensitive KW-2449 Preclinical - Patient cell culture Actionable In a preclinical study, FLT3-ITD mutations correlated with sensitivity to KW-2449 in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
FLT3 exon 14 ins NPM1 mutant acute myeloid leukemia predicted - sensitive Sorafenib Preclinical - Patient cell culture Actionable In a preclinical study, co-occurrence of FLT3-ITD and NPM1 mutations correlated with sensitivity to Nexavar (sorafenib) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
DNMT3A mut FLT3 exon 14 ins NPM1 mut acute myeloid leukemia predicted - sensitive Entospletinib Preclinical - Patient cell culture Actionable In a preclinical study, co-occurrence of FLT3-ITD, DNMT3A, and NPM1 mutations correlated with sensitivity to Entospletinib in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
DNMT3A mut NPM1 mut acute myeloid leukemia predicted - sensitive Entospletinib Preclinical - Patient cell culture Actionable In a preclinical study, co-occurrence of DNMT3A and NPM1 mutations correlated with sensitivity to Entospletinib in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
DNMT3A mut FLT3 exon 14 ins NPM1 mut acute myeloid leukemia predicted - sensitive Ibrutinib Preclinical - Patient cell culture Actionable In a preclinical study, co-occurrence of FLT3-ITD , DNMT3A, and NPM1 mutations correlated with sensitivity to Imbruvica (ibrutinib) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
NRAS mutant acute myeloid leukemia predicted - resistant Pazopanib Preclinical - Patient cell culture Actionable In a preclinical study, NRAS mutations correlated with resistance to Votrient (pazopanib) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
FLT3 exon 14 ins acute myeloid leukemia sensitive Crenolanib Preclinical - Patient cell culture Actionable In a preclinical study, FLT3-ITD mutations correlated with sensitivity to Crenolanib in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
NRAS mutant acute myeloid leukemia predicted - resistant Tivozanib Preclinical - Patient cell culture Actionable In a preclinical study, NRAS mutations correlated with resistance to Tivozanib (AV-951) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
KRAS mutant acute myeloid leukemia predicted - resistant TAE684 Preclinical - Patient cell culture Actionable In a preclinical study, KRAS mutations correlated with resistance to TAE684 in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
BCOR mut RUNX1 mut acute myeloid leukemia predicted - sensitive Pyridone 6 Preclinical - Patient cell culture Actionable In a preclinical study, co-occurrence of BCOR and RUNX1 mutations correlated with sensitivity to Pyridone 6 (CMP6) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
BCOR mut RUNX1 mut acute myeloid leukemia predicted - sensitive Momelotinib Preclinical - Patient cell culture Actionable In a preclinical study, co-occurrence of BCOR and RUNX1 mutations correlated with sensitivity to Momelotinib (CYT387) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
NPM1 mutant acute myeloid leukemia predicted - sensitive Entospletinib Preclinical - Patient cell culture Actionable In a preclinical study, NPM1 mutations correlated with sensitivity to Entospletinib in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
FLT3 exon 14 ins acute myeloid leukemia predicted - sensitive Ibrutinib Preclinical - Patient cell culture Actionable In a preclinical study, FLT3-ITD mutations correlated with sensitivity to Imbruvica (ibrutinib) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
KRAS mutant acute myeloid leukemia predicted - resistant Crizotinib Preclinical - Patient cell culture Actionable In a preclinical study, KRAS mutations correlated with resistance to Xalkori (crizotinib) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
NPM1 mutant acute myeloid leukemia predicted - sensitive Ibrutinib Preclinical - Patient cell culture Actionable In a preclinical study, NPM1 mutations correlated with sensitivity to Imbruvica (ibrutinib) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627
NRAS mutant acute myeloid leukemia predicted - resistant Vemurafenib Preclinical - Patient cell culture Actionable In a preclinical study, NRAS mutations correlated with resistance to Zelboraf (vemurafenib) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). 30333627