# Targeting TET DNA Dioxygenases as Therapeutic Principle in Myeloid Neoplasms

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $608,324

## Abstract

PROJECT SUMMARY/ABSTRACT
Ten Eleven Translocation (TET1, TET2 and TET3) are α-ketoglutarate (αKG) and Fe2+ dependent DNA-
dioxygenases that is a key regulator of epigenetic landscape. These enzymes progressively oxidize 5-
methylcytosine to 5-hydroxymethylcytosine and further to 5-formylcytosine and 5-carboxylcytosine in DNA
culminating into DNA demethylation essential for efficient transcription over large time scales. Loss-of-function
TET2 mutations (TET2MT), is one of the most frequent pathogenic lesion in MDS and related hematologic
malignancies in humans. TET2MT are found in all disease stages and levels of aggressiveness. In addition, recent
studies have demonstrated that somatic TET2MT are very frequently found in “healthy” elderly. The presence of
TET2MT in CHIP implies that it is an early event in the creation of hematologic disorders. It also supports murine
study conclusions that TET2MT cause expansions of hematopoietic stem and progenitor cells (HSPC). Early
events in the evolution of defective clones are rational targets for preventative strategies since clones in such
stages are likely to be dependent on these events. Their presence in all cells can, however, also be exploited in
late stages of the disease. For example, the combined loss of TET1 and TE2 in hematopoietic cells in murine
models extends life substantially relative to TET2 loss alone. In addition, the proof of principle is also derived
from observation in patients with IDH1/2MT whereby, these neomorphic mutations lead to the production of a
weak TET inhibitor, 2-hydroxyglutyrate (2-HG), known inhibitor of dioxygenases. Our observations that IDH1/2MT
are mutually exclusive with TET2MT, strongly supports our hypotheses that the TET inhibitor, 2-HG, prevents
evolution of TET2MT clones. This observation was further substantiated in a cellular model of myeloid malignant
cells and supports that synthetic lethality can be achieved through elimination of remaining TET-activity essential
for efficient transcription for proliferation in TET-dioxygenase deficient TET2MT clones.
Our overarching hypothesis is that rationally designed and synthesized small molecules TETi76 can be utilized
to impede compensatory TET dioxygenase activity originating from TET3 and TET1, to cause either synthetic
lethality or lineage redirection in cases with TET2MT inactivation. Our goal is to develop a novel therapeutic
approach for TET2MT MDS by evaluating the potential use of TETi76 as targeted treatments in preclinical models.
More specifically, we aim to: i) Study the mechanistic consequences of TET inhibition in normal and malignant
hematopoiesis in vitro. ii) Establish the effects of TETi compounds in vitro using human and murine cellular
models and iii) Characterize TETi preventative and therapeutic efficacy as well as tolerability in pre-clinical
murine models.
Our proposal, if successful, will lead to a novel class of therapeutic agents for TET2MT associated hematopoietic
disorders, and perhap...

## Key facts

- **NIH application ID:** 10317562
- **Project number:** 1R01CA257544-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Babal K Jha
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $608,324
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317562

## Citation

> US National Institutes of Health, RePORTER application 10317562, Targeting TET DNA Dioxygenases as Therapeutic Principle in Myeloid Neoplasms (1R01CA257544-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10317562. Licensed CC0.

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