The identification of TET2 mutations and the subsequent discovery of DNMT3a and IDH1/2 mutations in myeloid malignancies has led to the realization that dynamic changes in DNA methylation patterns induced by somatic mutations are critical to hematopoietic transformation. The TET proteins are iron/?-ketoglutarate (Fe++/?-KG)-dependent dioxygenases and are able to modify 5-methylcytosine (5mC) on DNA to 5- hydroxy/formyl/carboxly-cytosine (5hmC, 5fC, 5caC), which leads to subsequent DNA demethylation. TET2 is targeted by somatic mutations in a spectrum of myeloid malignancies, including 10-20% of AML. Our laboratories have led studies characterizing the mutational spectra of TET2 in myeloid leukemias and in in vivo studies demonstrating that TET2 is a haploinsufficient tumor suppressor, which increases hematopoietic stem cell self-renewal and myeloid transformation. Supported by this award we were able to study in detail TET2 function in leukemia. We identified TET2 interacting proteins, generated disease models by modeling Tet2 alterations in concert with co-occurring myeloid disease alleles, delineated the relative role of Tet1 and Tet2 in hematopoietic function, employed techniques to map TET2-mediated 5hmC deposition at a genome-wide scale, and restored Tet2 activity in animal models and identified compounds that can target TET2-mutant myeloid leukemia. Moreover, we were able to show that TET2 mutations are an initiating event in clonal hematopoiesis (CH) that then ?seeds? the ground for additional somatic alterations, which then drive progression to myeloid transformation. This places us in an excellent position to address significant new questions relating to the molecular roles of TET2 in the initiation and progression of myeloid leukemia: 1) Are mutational order and/or cell compartment which acquires TET2/cooperating mutations critical in myeloid transformation? 2) Can we suppress disease progression, even in the presence of additional mutational events, if we restore wild-type TET2 expression and function? 3) Are there functional differences between TET2 loss and TET2 missense mutations that are seen in a subset of leukemia patients? We will address these important questions through the use of state-of-the art mouse models, epigenomic profiling techniques, and studies in primary patient samples to elucidate novel mechanisms of TET2-mediated transformation.
The identification of TET2 mutations led to the realization that dynamic changes in DNA methylation patterns induced by acquired mutations are critical to hematopoietic transformation. We will use of state-of-the art mouse models, epigenomic profiling techniques, and studies in primary patient samples to elucidate novel mechanisms of TET2-mediated transformation in blood cancers.
|Bowman, Robert L; Busque, Lambert; Levine, Ross L (2018) Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies. Cell Stem Cell 22:157-170|
|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|
|Kleppe, Maria; Spitzer, Matthew H; Li, Sheng et al. (2018) Jak1 Integrates Cytokine Sensing to Regulate Hematopoietic Stem Cell Function and Stress Hematopoiesis. Cell Stem Cell 22:277|
|Kourtis, Nikos; Lazaris, Charalampos; Hockemeyer, Kathryn et al. (2018) Oncogenic hijacking of the stress response machinery in T cell acute lymphoblastic leukemia. Nat Med 24:1157-1166|
|Cimmino, Luisa; Neel, Benjamin G; Aifantis, Iannis (2018) Vitamin C in Stem Cell Reprogramming and Cancer. Trends Cell Biol 28:698-708|
|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|
|Wang, Eric; Aifantis, Ioannis (2017) Targeting the Noncoding Genome: Superenhancers Meet Their Kryptonite. Cancer Discov 7:1065-1066|
|Kleppe, Maria; Spitzer, Matthew H; Li, Sheng et al. (2017) Jak1 Integrates Cytokine Sensing to Regulate Hematopoietic Stem Cell Function and Stress Hematopoiesis. Cell Stem Cell 21:489-501.e7|
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