title: Chemo-genomic interrogation of CEBPA mutated AML reveals recurrent CSF3R mutations and subgroup sensitivity to JAK inhibitors.
abstract: In this study, we analyzed RNA-sequencing data of 14 samples characterized by biallelic CEBPA (CEBPA(bi)) mutations included in the Leucegene collection of 415 primary acute myeloid leukemia (AML) specimens, and describe for the first time high frequency recurrent mutations in the granulocyte colony-stimulating factor receptor gene CSF3R, which signals through JAK-STAT proteins. Chemical interrogation of these primary human specimens revealed a uniform and specific sensitivity to all JAK inhibitors tested irrespective of their CSF3R mutation status, indicating a general sensitization of JAK-STAT signaling in this leukemia subset. Altogether, these results identified the co-occurrence of mutations in CSF3R and CEBPA in a well-defined AML subset, which uniformly responds to JAK inhibitors and paves the way to personalized clinical trials for this disease.
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada;
authors.forename: Vincent-Philippe
authors.identifier: 0000-0001-9095-0066
authors.initials: VP
authors.lastname: Lavallée
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada;
authors.forename: Jana
authors.initials: J
authors.lastname: Krosl
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada; Department of Computer Science and Operations Research, and.
authors.forename: Sébastien
authors.identifier: 0000-0001-5477-1386
authors.initials: S
authors.lastname: Lemieux
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada;
authors.forename: Geneviève
authors.identifier: 0000-0001-6389-9007
authors.initials: G
authors.lastname: Boucher
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada;
authors.forename: Patrick
authors.initials: P
authors.lastname: Gendron
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada;
authors.forename: Caroline
authors.identifier: 0000-0001-9716-5909
authors.initials: C
authors.lastname: Pabst
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada;
authors.forename: Isabel
authors.initials: I
authors.lastname: Boivin
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada; Department of Chemistry, Université de Montréal, Montréal, QC, Canada;
authors.forename: Anne
authors.initials: A
authors.lastname: Marinier
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada;
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Guidos
authors.affiliation: Department of Pharmacology, and Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada;
authors.forename: Sylvain
authors.initials: S
authors.lastname: Meloche
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada; Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada; and Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
authors.forename: Josée
authors.initials: J
authors.lastname: Hébert
authors.affiliation: The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada; Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada; and Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Sauvageau
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D057285:Precision Medicine; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics*; D059467:Transcriptome; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C517047:CSF3R protein, human; D047428:Protein Kinase Inhibitors; D016184:Receptors, Colony-Stimulating Factor; D053612:Janus Kinases