Acute myeloid leukemia (AML) is the most common acute leukemia seen in adults, and despite considerable efforts, this malignancy is still associated with poor outcomes and limited therapeutic options. TET2 (Ten Eleven Translocation 2) is a gene mutated in 10-25% of various hematologic malignancies. In AML, its mutation confers poorer prognosis. TET2 functions to modify DNA and belongs to a new class of genes known as epigenetic modifiers. These new genes are being implicated in a wide range of malignancies and are novel targets of therapy.
The aims of this project are to 1) Identify target genes of TET2 activity and epigenetic changes due to TET2 loss 2) Determine the in vivo effects of drug treatment in Tet2 mutant mouse models, and 3) Screen for new therapeutic targets and strategies inTET2 mutant leukemia. Preliminary data demonstrate that loss of TET2 function leads to increased proliferation of stem cells, changes in epigenetic modifications, and alteration of gene expression patterns. This project proposes experiments using chromatin immunoprecipitation, methylation profiling, RNA profiling, multiparameter flow cytometry, and shRNA screening to understand the specific gene changes leading to leukemia. The research is supported by collaborations with the He laboratory at University of Chicago and Melnick laboratory at Weill Cornell, both with expertise in genomic profiling. Experiments using mouse models will determine in vivo effects leading to leukemogenesis and treatment response and resistance. Understanding of TET2 function will lead to better understanding of disease mechanisms and new modes of therapy. Alan Shih, an Instructor at MSKCC, will conduct this project as part of a career development plan, dedicating 80% of his time to research with remainder spent on clinical leukemia work. MSKCC is a leading cancer center with in-depth clinical expertise closely allied with translational and basic science research with state-of-the-at abilities. Alan is mentored by Dr. Ross Levine, a world expert in hematologic malignancies. He is also advised by Dr. Scott Lowe and Dr. Scott Armstrong at MSKCC, and Dr.Ari Melnick at Weill Cornell. Alan's training will include gaining technical laboratory skills, knowledge in the epigenetic research field, formal presentation experience, and practical experience in bioinformatics. In the short term, the project goal is to publish a paper on the findings from this research. In the long term, the goal is for developing a research program to become an independent laboratory investigator in hematologic malignancies.

Public Health Relevance

Acute Myeloid Leukemia is a hematologic malignancy with poor treatment outcomes, and a subset of patients with mutations in the gene TET2 was found to have worse prognosis. Preliminary data have identified potential mechanisms in which mutations in TET2 leads to changes in hematopoietic development and leukemogenesis. This grant aims to use mouse models and basic molecular techniques to better understand the role TET2 mutations play in leukemogenesis and in response and resistance to therapy, and also to screen for new treatment targets based on this mutation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Clinical Investigator Award (CIA) (K08)
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Study Section
Subcommittee I - Transistion to Independence (NCI)
Program Officer
Bian, Yansong
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Icahn School of Medicine at Mount Sinai
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Intlekofer, Andrew M; Shih, Alan H; Wang, Bo et al. (2018) Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations. Nature 559:125-129
McKenney, Anna Sophia; Lau, Allison N; Somasundara, Amritha Varshini Hanasoge et al. (2018) JAK2/IDH-mutant-driven myeloproliferative neoplasm is sensitive to combined targeted inhibition. J Clin Invest 128:789-804
Harding, James J; Lowery, Maeve A; Shih, Alan H et al. (2018) Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition. Cancer Discov 8:1540-1547
Kleppe, Maria; Koche, Richard; Zou, Lihua et al. (2018) Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms. Cancer Cell 33:29-43.e7
Kunimoto, Hiroyoshi; Meydan, Cem; Nazir, Abbas et al. (2018) Cooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity. Cancer Cell 33:44-59.e8
Shih, Alan H; Meydan, Cem; Shank, Kaitlyn et al. (2017) Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in IDH2- and TET2-Mutant Acute Myeloid Leukemia. Cancer Discov 7:494-505
Kunimoto, Hiroyoshi; McKenney, Anna Sophia; Meydan, Cem et al. (2017) Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells. Blood 129:1779-1790
Amatangelo, Michael D; Quek, Lynn; Shih, Alan et al. (2017) Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood 130:732-741