Recent studies have identified global and subset specific epigenetic alterations in AML patients with biologic and prognostic value. Recent studies have identified somatic mutations in known and putative epigenetic modifiers, including TET2, which encodes an enzyme which adds hydroxyl groups to 5-methylcytosine and leads to subsequent DNA hypomethylation. Importantly TET2 mutations are recurrent in AML and are associated with adverse outcome. These studies raise the possibility that TET2 and other mutations in epigenetic modifiers contribute to hematopoietic transformation through dysregulation of the epigenetic state in hematopoietic cells. We hypothesize that there are genetic and epigenetic alterations affecting master regulators of the epigenetic state, and that these specific alterations affect hematopoietic transformation through discrete modifications of the epigenetic state of specific target genes. We propose that TET2 is one such epigenetic regulator. We will assess the role of TET2 mutations in AML pathogenesis in studies in primary AML samples and in our novel, conditional knockout model of TET2 which implicates TET2 in stem cell self-renewal and myeloid transformation.
The specific aims of this proposal will 1) assess the effects of mutant TET2 on the epigenetic state and gene expression in normal/malignant stem/progenitor cells using state-of-the-art next generation sequencing technologies. We will also 2) assess the effects of TET2 loss on myeloid transformation in vivo and develop novel, TET2-dependent AML models for biologic and therapeutic studies. Finally, given our preliminary data suggests that TET2 mutations are associated with poor outcome and increased relapse rate, we will 3) investigate the basis for the poor response of TET2-mutant AML to chemotherapy and test combination cytotoxic/epigenetic therapy as an alternate therapeutic strategy for this genetically defined subset of AML.

Public Health Relevance

Although most patients with acute myeloid leukemia (AML) respond to initial cytotoxic chemotherapy, the majority of patients die from their disease due to the high rate of relapse. Importantly, genetic and epigenetic studies have AML is a heterogeneous disease in which different genetic and epigenetic alterations greatly affect disease outcome. We believe our studies will provide important insight into the molecular basis of a genetically defined subset of patients with high risk AML, and provide therapeutic options for patients with TET2-mutant AML and with other forms of high risk leukemia which are not cured by current therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA173636-01
Application #
8434414
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mufson, R Allan
Project Start
2013-02-07
Project End
2018-01-31
Budget Start
2013-02-07
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$626,964
Indirect Cost
$137,517
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Cimmino, Luisa; Aifantis, Iannis (2016) Alternative roles for oxidized mCs and TETs. Curr Opin Genet Dev 42:1-7
Inoue, Satoshi; Li, Wanda Y; Tseng, Alan et al. (2016) Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2. Cancer Cell 30:337-48
King, Bryan; Boccalatte, Francesco; Moran-Crusio, Kelly et al. (2016) The ubiquitin ligase Huwe1 regulates the maintenance and lymphoid commitment of hematopoietic stem cells. Nat Immunol 17:1312-1321
Strikoudis, Alexandros; Lazaris, Charalampos; Trimarchi, Thomas et al. (2016) Regulation of transcriptional elongation in pluripotency and cell differentiation by the PHD-finger protein Phf5a. Nat Cell Biol 18:1127-1138
Coombs, Catherine C; Sallman, David A; Devlin, Sean M et al. (2016) Mutational correlates of response to hypomethylating agent therapy in acute myeloid leukemia. Haematologica 101:e457-e460
Guillamot, Maria; Cimmino, Luisa; Aifantis, Iannis (2016) The Impact of DNA Methylation in Hematopoietic Malignancies. Trends Cancer 2:70-83
Han, Dali; Lu, Xingyu; Shih, Alan H et al. (2016) A Highly Sensitive and Robust Method for Genome-wide 5hmC Profiling of Rare Cell Populations. Mol Cell 63:711-9
Aranda-Orgilles, Beatriz; Saldaña-Meyer, Ricardo; Wang, Eric et al. (2016) MED12 Regulates HSC-Specific Enhancers Independently of Mediator Kinase Activity to Control Hematopoiesis. Cell Stem Cell 19:784-799
Ntziachristos, Panagiotis; Abdel-Wahab, Omar; Aifantis, Iannis (2016) Emerging concepts of epigenetic dysregulation in hematological malignancies. Nat Immunol 17:1016-24
Guryanova, O A; Lieu, Y K; Garrett-Bakelman, F E et al. (2016) Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells. Leukemia 30:1133-42

Showing the most recent 10 out of 47 publications