Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia

Alan H Shih; Yanwen Jiang; Cem Meydan; Kaitlyn Shank; Suveg Pandey; Laura Barreyro; Ileana Antony-Debre; Agnes Viale; Nicholas Socci; Yongming Sun; Alexander Robertson; Magali Cavatore; Elisa de Stanchina; Todd Hricik; Franck Rapaport; Brittany Woods; Chen Wei; Megan Hatlen; Muhamed Baljevic; Stephen D Nimer; Martin Tallman; Elisabeth Paietta; Luisa Cimmino; Iannis Aifantis; Ulrich Steidl; Chris Mason; Ari Melnick; Ross L Levine

doi:10.1016/j.ccell.2015.03.009

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Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia

Journal article

Open access

Peer reviewed

Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia

Alan H Shih, Yanwen Jiang, Cem Meydan, Kaitlyn Shank, Suveg Pandey, Laura Barreyro, Ileana Antony-Debre, Agnes Viale, Nicholas Socci, Yongming Sun, …

Cancer cell, Vol.27(4), pp.502-515

2015-04-13

DOI: https://doi.org/10.1016/j.ccell.2015.03.009

PMCID: PMC4518555

PMID: 25873173

Abstract

Proto-Oncogene Proteins - metabolism

Doxorubicin - therapeutic use

Cytarabine - therapeutic use

Epigenesis, Genetic

Gene Expression Regulation, Neoplastic

Gene Silencing

Proto-Oncogene Proteins - genetics

Antineoplastic Agents - therapeutic use

DNA-Binding Proteins - genetics

fms-Like Tyrosine Kinase 3 - metabolism

Haploinsufficiency

DNA-Binding Proteins - metabolism

fms-Like Tyrosine Kinase 3 - genetics

Cell Differentiation - genetics

DNA Methylation

Mutation

GATA2 Transcription Factor - genetics

Leukemia, Myeloid, Acute - genetics

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.

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Collaboration types: Industry collaboration; Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.103 Blood Disorders; 1.103.155 Acute Myeloid Leukemia
Web Of Science research areas: Cell Biology; Oncology
ESI research areas: Molecular Biology & Genetics

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Title: Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia
Creators: Alan H Shih - 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
Yanwen Jiang - 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
Cem Meydan - Institute for Computational Biomedicine and Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA
Kaitlyn Shank - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Suveg Pandey - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Laura Barreyro - Department of Cell Biology and Division of Hematologic Malignancies, Department of Medicine (Oncology), Albert Einstein College of Medicine, New York, NY 10461, USA
Ileana Antony-Debre - Department of Cell Biology and Division of Hematologic Malignancies, Department of Medicine (Oncology), Albert Einstein College of Medicine, New York, NY 10461, USA
Agnes Viale - Genomics Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Nicholas Socci - Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Yongming Sun - Life Technologies, South San Francisco, CA 94080, USA
Alexander Robertson - Life Technologies, South San Francisco, CA 94080, USA
Magali Cavatore - Genomics Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Elisa de Stanchina - Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Todd Hricik - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Franck Rapaport - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Brittany Woods - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Chen Wei - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Megan Hatlen - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Muhamed Baljevic - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Stephen D Nimer - Sylvester Cancer Center, University of Miami, Miami, FL 33136, USA
Martin Tallman - Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Elisabeth Paietta - Department of Oncology, Montefiore Hospital, Bronx, NY 10467, USA
Luisa Cimmino - Department of Pathology and Howard Hughes Medical Institute, NYU School of Medicine, New York, NY 10016, USA
Iannis Aifantis - Department of Pathology and Howard Hughes Medical Institute, NYU School of Medicine, New York, NY 10016, USA
Ulrich Steidl - Department of Cell Biology and Division of Hematologic Malignancies, Department of Medicine (Oncology), Albert Einstein College of Medicine, New York, NY 10461, USA
Chris Mason - Institute for Computational Biomedicine and Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA
Ari Melnick - 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
Ross L Levine - 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
Publication Details: Cancer cell, Vol.27(4), pp.502-515
Publisher: United States
Grant note: U10 CA021115 / NCI NIH HHS R01 CA173636 / NCI NIH HHS R01CA166835 / NCI NIH HHS U10 CA180827 / NCI NIH HHS R01 HG006798 / NHGRI NIH HHS R01HG006798 / NHGRI NIH HHS CA172636-01 / NCI NIH HHS R01 CA166835 / NCI NIH HHS P30 CA008748 / NCI NIH HHS R01 NS076465 / NINDS NIH HHS U10 CA180820 / NCI NIH HHS R01NS076465 / NINDS NIH HHS R01 CA166429 / NCI NIH HHS U24 CA196172 / NCI NIH HHS R01 CA169784 / NCI NIH HHS P30 CA013330 / NCI NIH HHS
Academic Unit: Leadership Department; Miller School of Medicine; Biochemistry & Molecular Biology Research; Sylvester Comprehensive Cancer Center
Language: English
Resource Type: Journal article
PMID: 25873173
PMCID: PMC4518555
Record Identifier: 991031560504302976