# Role of TET2 mutations in malignant transformation and acute myeloid leukemia

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $639,187

## Abstract

PROJECT SUMMARY
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/α-ketoglutarate
(Fe++/α-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.

## Key facts

- **NIH application ID:** 9920686
- **Project number:** 5R01CA173636-08
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Iannis Aifantis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $639,187
- **Award type:** 5
- **Project period:** 2013-02-07 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920686

## Citation

> US National Institutes of Health, RePORTER application 9920686, Role of TET2 mutations in malignant transformation and acute myeloid leukemia (5R01CA173636-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9920686. Licensed CC0.

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