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	Vol	Issue	Date	Pages	Journal Short Title
Nature	562	7728	2018 10	526-531	Nature

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

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
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
NRAS mutant	acute myeloid leukemia	predicted - resistant	Tivozanib	Preclinical - Patient cell culture	Actionable	In a preclinical study, NRAS mutations correlated with resistance to Fotivda (tivozanib) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627).	30333627
FLT3 exon 14 ins	acute myeloid leukemia	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	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
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	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
FLT3 exon 14 ins	acute myeloid leukemia	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
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