title: Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia.
abstract: Specific combinations of acute myeloid leukemia (AML) disease alleles, including FLT3 and TET2 mutations, confer distinct biologic features and adverse outcome. We generated mice with mutations in Tet2 and Flt3, which resulted in fully penetrant, lethal AML. Multipotent Tet2(-/-);Flt3(ITD) progenitors (LSK CD48(+)CD150(-)) propagate disease in secondary recipients and were refractory to standard AML chemotherapy and FLT3-targeted therapy. Flt3(ITD) mutations and Tet2 loss cooperatively remodeled DNA methylation and gene expression to an extent not seen with either mutant allele alone, including at the Gata2 locus. Re-expression of Gata2 induced differentiation in AML stem cells and attenuated leukemogenesis. TET2 and FLT3 mutations cooperatively induce AML, with a defined leukemia stem cell population characterized by site-specific changes in DNA methylation and gene expression.
authors: Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Alan H
authors: AH
authors: Shih
authors: Institute for Computational Biomedicine and Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA; Department of Medicine/Hematology-Oncology and Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Yanwen
authors: Y
authors: Jiang
authors: Institute for Computational Biomedicine and Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Cem
authors: C
authors: Meydan
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Kaitlyn
authors: K
authors: Shank
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Suveg
authors: S
authors: Pandey
authors: Department of Cell Biology and Division of Hematologic Malignancies, Department of Medicine (Oncology), Albert Einstein College of Medicine, New York, NY 10461, USA.
authors: Laura
authors: L
authors: Barreyro
authors: Department of Cell Biology and Division of Hematologic Malignancies, Department of Medicine (Oncology), Albert Einstein College of Medicine, New York, NY 10461, USA.
authors: Ileana
authors: I
authors: Antony-Debre
authors: Genomics Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Agnes
authors: A
authors: Viale
authors: Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Nicholas
authors: N
authors: Socci
authors: Life Technologies, South San Francisco, CA 94080, USA.
authors: Yongming
authors: Y
authors: Sun
authors: Life Technologies, South San Francisco, CA 94080, USA.
authors: Alexander
authors: A
authors: Robertson
authors: Genomics Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Magali
authors: M
authors: Cavatore
authors: Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Elisa
authors: E
authors: de Stanchina
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Todd
authors: T
authors: Hricik
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Franck
authors: F
authors: Rapaport
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Brittany
authors: B
authors: Woods
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Chen
authors: C
authors: Wei
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Megan
authors: M
authors: Hatlen
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Muhamed
authors: M
authors: Baljevic
authors: Sylvester Cancer Center, University of Miami, Miami, FL 33136, USA.
authors: Stephen D
authors: SD
authors: Nimer
authors: Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Martin
authors: M
authors: Tallman
authors: Department of Oncology, Montefiore Hospital, Bronx, NY 10467, USA.
authors: Elisabeth
authors: E
authors: Paietta
authors: Department of Pathology and Howard Hughes Medical Institute, NYU School of Medicine, New York, NY 10016, USA.
authors: Luisa
authors: L
authors: Cimmino
authors: Department of Pathology and Howard Hughes Medical Institute, NYU School of Medicine, New York, NY 10016, USA.
authors: Iannis
authors: I
authors: Aifantis
authors: Department of Cell Biology and Division of Hematologic Malignancies, Department of Medicine (Oncology), Albert Einstein College of Medicine, New York, NY 10461, USA.
authors: Ulrich
authors: U
authors: Steidl
authors: Institute for Computational Biomedicine and Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Chris
authors: C
authors: Mason
authors: Department of Medicine/Hematology-Oncology and Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA; Weill Cornell Medical College, Cornell University, 413 E 69th Street, BB-1462, New York, NY 10021, USA. Electronic address: amm2014@med.cornell.edu.
authors: Ari
authors: A
authors: Melnick
authors: Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA. Electronic address: leviner@mskcc.org.
authors: Ross L
authors: RL
authors: Levine
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D002454:Cell Differentiation / Q000235:genetics; D003561:Cytarabine / Q000627:therapeutic use; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D049308:Dioxygenases; D004317:Doxorubicin / Q000627:therapeutic use; D044127:Epigenesis, Genetic; D050989:GATA2 Transcription Factor / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D057895:Haploinsufficiency; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D011518:Proto-Oncogene Proteins; D003561:Cytarabine; D004317:Doxorubicin; D049308:Dioxygenases; C551914:Tet2 protein, mouse; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3