title: Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms.
abstract: Patients with myeloproliferative neoplasms (MPNs) are at significant, cumulative risk of leukemic transformation to acute myeloid leukemia (AML), which is associated with adverse clinical outcome and resistance to standard AML therapies. We performed genomic profiling of post-MPN AML samples; these studies demonstrate somatic tumor protein 53 (TP53) mutations are common in JAK2V617F-mutant, post-MPN AML but not in chronic-phase MPN and lead to clonal dominance of JAK2V617F/TP53-mutant leukemic cells. Consistent with these data, expression of JAK2V617F combined with Tp53 loss led to fully penetrant AML in vivo. JAK2V617F-mutant, Tp53-deficient AML was characterized by an expanded megakaryocyte erythroid progenitor population that was able to propagate the disease in secondary recipients. In vitro studies revealed that post-MPN AML cells were sensitive to decitabine, the JAK1/2 inhibitor ruxolitinib, or the heat shock protein 90 inhibitor 8-(6-iodobenzo[d][1.3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purine-6-amine (PU-H71). Treatment with ruxolitinib or PU-H71 improved survival of mice engrafted with JAK2V617F-mutant, Tp53-deficient AML, demonstrating therapeutic efficacy for these targeted therapies and providing a rationale for testing these therapies in post-MPN AML.
authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service.
authors.forename: Raajit
authors.initials: R
authors.lastname: Rampal
authors.affiliation: Human Oncology and Pathogenesis Program.
authors.forename: Jihae
authors.initials: J
authors.lastname: Ahn
authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA 02139; and.
authors.forename: Michelle
authors.initials: M
authors.lastname: Nahas
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA 02139; and.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA 02139; and.
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA 02139; and.
authors.forename: Geoff A
authors.initials: GA
authors.lastname: Otto
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA 02139; and.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: Human Oncology and Pathogenesis Program.
authors.forename: Todd
authors.initials: T
authors.lastname: Hricik
authors.affiliation: Human Oncology and Pathogenesis Program.
authors.forename: Anna Sophia
authors.initials: AS
authors.lastname: McKenney
authors.affiliation: Program in Molecular Pharmacology and Chemistry, Medicine.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
authors.affiliation: Human Oncology and Pathogenesis Program.
authors.forename: Young Rock
authors.initials: YR
authors.lastname: Chung
authors.affiliation: Human Oncology and Pathogenesis Program.
authors.forename: Suveg
authors.initials: S
authors.lastname: Pandey
authors.affiliation: Medicine, Departments of Immunology.
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
authors.affiliation: Human Oncology and Pathogenesis Program, Pediatrics, and.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.affiliation: Pathology, and.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Dogan
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;
authors.forename: Andrew
authors.initials: A
authors.lastname: Intlekofer
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Taghi
authors.initials: T
authors.lastname: Manshouri
authors.affiliation: Human Oncology and Pathogenesis Program, Pathology, and.
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Park
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.affiliation: Human Oncology and Pathogenesis Program.
authors.forename: Franck
authors.initials: F
authors.lastname: Rapaport
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA 02139; and.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA 02139; and.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service, leviner@mskcc.org.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D015153:Blotting, Western; D003114:Colony-Forming Units Assay; D000077209:Decitabine; D059472:Exome / Q000235:genetics; D005434:Flow Cytometry; D019337:Hematologic Neoplasms / Q000150:complications*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D051379:Mice; D020125:Mutation, Missense / Q000235:genetics; D009196:Myeloproliferative Disorders / Q000150:complications* / Q000235:genetics*; D009570:Nitriles; D011687:Purines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D052117:Benzodioxoles; D009570:Nitriles; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C526550:9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-; D000077209:Decitabine; C540383:ruxolitinib; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D001374:Azacitidine
keywords: cancer biology; genetics; leukemia; myeloproliferative neoplasm; targeted therapy