title: Genomics of primary chemoresistance and remission induction failure in paediatric and adult acute myeloid leukaemia.
abstract: Cure rates of children and adults with acute myeloid leukaemia (AML) remain unsatisfactory partly due to chemotherapy resistance. We investigated the genetic basis of AML in 107 primary cases by sequencing 670 genes mutated in haematological malignancies. SETBP1, ASXL1 and RELN mutations were significantly associated with primary chemoresistance. We identified genomic alterations not previously described in AML, together with distinct genes that were significantly overexpressed in therapy-resistant AML. Defined gene mutations were sufficient to explain primary induction failure in only a minority of cases. Thus, additional genetic or molecular mechanisms must cause primary chemoresistance in paediatric and adult AML.
authors.affiliation: Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Fiona C
authors.initials: FC
authors.lastname: Brown
authors.affiliation: Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cifani
authors.affiliation: Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Esther
authors.initials: E
authors.lastname: Drill
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: He
authors.affiliation: Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Still
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Zhong
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Sohail
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Dean
authors.initials: D
authors.lastname: Pavlick
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Bahar
authors.initials: B
authors.lastname: Yilmazel
authors.affiliation: Leukemia Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Knapp
authors.affiliation: Children's Oncology Group, Monrovia, CA, USA.|Department of Biostatistics, University of Southern California, Los Angeles, CA, USA.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Alonzo
authors.affiliation: Children's Oncology Group, Monrovia, CA, USA.|Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Soheil
authors.initials: S
authors.lastname: Meshinchi
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.affiliation: Department of Leukemia, The University of Texas and MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Gehr Family Leukemia Center, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: Children's Oncology Group, Monrovia, CA, USA.|Division of Hematology-Oncology, Children's Mercy Hospitals and Clinics, Kansas City, MO, USA.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Gamis
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Mithat
authors.initials: M
authors.lastname: Gonen
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY, USA.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Pediatrics, Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY, USA.
authors.forename: Alex
authors.identifier: http://orcid.org/0000-0002-8063-9191
authors.initials: A
authors.lastname: Kentsis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000235:genetics; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D023281:Genomics / Q000379:methods*; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D011247:Pregnancy; D000091042:Reelin Protein; D012074:Remission Induction / Q000379:methods; D012097:Repressor Proteins / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D017211:Treatment Failure; D055815:Young Adult
chemical_list: C473949:ASXL1 protein, human; D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000091042:Reelin Protein; D012097:Repressor Proteins; C425066:SETBP1 protein, human; C000717127:RELN protein, human; D012697:Serine Endopeptidases
keywords: cytogenetically normal acute myeloid leukaemia; induction failure; paediatric leukaemia; primary chemoresistance; targeted deep sequencing genomics