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Cancer Cell. 2015 Apr 13;27(4):502-15. doi: 10.1016/j.ccell.2015.03.009.

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

Author information

1
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.
2
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.
3
Institute for Computational Biomedicine and Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
4
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5
Department of Cell Biology and Division of Hematologic Malignancies, Department of Medicine (Oncology), Albert Einstein College of Medicine, New York, NY 10461, USA.
6
Genomics Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
7
Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
8
Life Technologies, South San Francisco, CA 94080, USA.
9
Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
10
Sylvester Cancer Center, University of Miami, Miami, FL 33136, USA.
11
Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
12
Department of Oncology, Montefiore Hospital, Bronx, NY 10467, USA.
13
Department of Pathology and Howard Hughes Medical Institute, NYU School of Medicine, New York, NY 10016, USA.
14
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.
15
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.

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.

PMID:
25873173
PMCID:
PMC4518555
DOI:
10.1016/j.ccell.2015.03.009
[Indexed for MEDLINE]
Free PMC Article

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