title: Therapeutically Targetable ALK Mutations in Leukemia.
abstract: Genome sequencing is revealing a vast mutational landscape in leukemia, offering new opportunities for treatment with targeted therapy. Here, we identify two patients with acute myelogenous leukemia and B-cell acute lymphoblastic leukemia whose tumors harbor point mutations in the ALK kinase. The mutations reside in the extracellular domain of ALK and are potently transforming in cytokine-independent cellular assays and primary mouse bone marrow colony formation studies. Strikingly, both mutations conferred sensitivity to ALK kinase inhibitors, including the FDA-approved drug crizotinib. On the basis of our results, we propose that tumors harboring ALK mutations may be therapeutically tractable for personalized treatment of certain aggressive leukemias with ALK inhibitors.
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Maxson
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Division of Hematology and Oncology, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon.
authors.forename: Monika A
authors.initials: MA
authors.lastname: Davare
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon.
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Luty
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon. Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Eide
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Division of Hematology and Oncology, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon.
authors.forename: Bill H
authors.initials: BH
authors.lastname: Chang
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon.
authors.forename: Marc M
authors.initials: MM
authors.lastname: Loriaux
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon. Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Cristina E
authors.initials: CE
authors.lastname: Tognon
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Oregon Clinical and Translational Research Institute, Oregon Health and Science University, Portland, Oregon.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bottomly
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Oregon Clinical and Translational Research Institute, Oregon Health and Science University, Portland, Oregon. Division of Bioinformatics and Computational Biology, Oregon Health and Science University, Portland, Oregon.
authors.forename: Beth
authors.initials: B
authors.lastname: Wilmot
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Oregon Clinical and Translational Research Institute, Oregon Health and Science University, Portland, Oregon. Division of Bioinformatics and Computational Biology, Oregon Health and Science University, Portland, Oregon.
authors.forename: Shannon K
authors.initials: SK
authors.lastname: McWeeney
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon. Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon. tynerj@ohsu.edu.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation; D057285:Precision Medicine; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases