Chemo-genomic interrogation of CEBPA mutated AML reveals recurrent CSF3R mutations and subgroup sensitivity to JAK inhibitors

Vincent-Philippe Lavallée; Jana Krosl; Sébastien Lemieux; Geneviève Boucher; Patrick Gendron; Caroline Pabst; Isabel Boivin; Anne Marinier; Cynthia J Guidos; Sylvain Meloche; Josée Hébert; Guy Sauvageau

doi:10.1182/blood-2016-03-705053

Chemo-genomic interrogation of CEBPA mutated AML reveals recurrent CSF3R mutations and subgroup sensitivity to JAK inhibitors

Blood. 2016 Jun 16;127(24):3054-61. doi: 10.1182/blood-2016-03-705053. Epub 2016 Mar 31.

Affiliations

¹ 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;
² The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada;
³ 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.
⁴ 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;
⁵ 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;
⁶ Department of Pharmacology, and Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada;
⁷ 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.

PMID: 27034432
DOI: 10.1182/blood-2016-03-705053

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
CCAAT-Enhancer-Binding Proteins / genetics*
Cohort Studies
DNA Mutational Analysis / methods
Drug Resistance, Neoplasm / genetics*
Drug Screening Assays, Antitumor
Female
Gene Expression Profiling
Gene Frequency
High-Throughput Nucleotide Sequencing
Humans
Janus Kinases / antagonists & inhibitors*
Leukemia, Myeloid, Acute / classification
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / pathology
Male
Middle Aged
Mutation
Precision Medicine
Protein Kinase Inhibitors / therapeutic use*
Receptors, Colony-Stimulating Factor / genetics*
Transcriptome
Tumor Cells, Cultured
Young Adult

Substances

CCAAT-Enhancer-Binding Proteins
CEBPA protein, human
CSF3R protein, human
Protein Kinase Inhibitors
Receptors, Colony-Stimulating Factor
Janus Kinases