# Targeting TET1 signaling to treat acute myeloid leukemia

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2021 · $457,310

## Abstract

Background: Acute myeloid leukemia (AML) is a common disease with over 70% of patients cannot be cured.
Thus, it is urgent to develop effective new therapies. The TET (TET1/2/3) proteins are a family of
methylcytosine dioxygenases involving DNA demethylation. In contrast to the tumor-suppressor roles of TET
genes reported previously, we found that TET1 is significantly up-regulated and functions as a critical
oncogene in MLL-rearranged AMLs (Huang et al. PNAS, 2013). We have recently found that TET1 is also up-
regulated in AMLs carrying t(8;21), in which TET1 likely also plays an essential oncogenic role. Moreover, we
have identified NSC-370284 as a lead small-molecule compound that selectively represses TET1 signaling
and effectively inhibits growth of AML cells with a high level of endogenous TET1 expression.
 Hypothesis: TET1 plays a critical oncogenic role in the pathogenesis of not only MLL-rearranged AMLs
but also t(8;21) AMLs, and targeting TET1 signaling by selective small-molecule compound(s) represents an
effective novel therapeutic strategy to treat these AMLs.
 Specific Aims: 1) To determine the definitive role of TET1 in both development and maintenance of t(8;21)
AMLs, and identify critical target genes of TET1 in t(8;21) AMLs; 2) To decipher the molecular mechanism by
which the lead compound (NSC-370284) inhibits TET1 signaling and exhibits an anti-leukemia activity; and 3)
To develop novel therapies targeting TET1 signaling to treat MLL-rearranged AMLs and t(8;21) AMLs.
 Study Design: 1) First, to determine the role of TET1 in both development and maintenance of the major
subtypes of t(8;21) AMLs, we will conduct both primary and secondary mouse bone marrow transplantation
(BMT) assays using wild-type and Tet1 knockout mouse models together with retrovirally induced major
subtypes of t(8;21) AML models. Second, to identify critical target genes of TET1 in t(8;21) AML, ChIP-Seq,
5hmC-Seq and RNA-Seq will be conducted. 2) Our preliminary data suggests that NSC-370284 likely targets
SATA5 directly and thereby inhibits TET1 transcription. Here we will conduct a series of structural-functional
studies, biochemical and pharmaceutical assays, and gene transcriptional regulation assays to determine
whether STAT5 is a critical direct target of NSC-370284 and also a direct upstream regulator of TET1.
Meanwhile, we will also conduct a series of assays to identify other potential direct targets of NSC-370284. 3)
We will first assess pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) and
toxicity profile of NSC-370284 in vivo. We will then employ a series of preclinical animal models to evaluate the
therapeutic efficacy and potential of NSC-370284, alone and especially together with other therapeutic
agent(s), in treating both MLL-rearranged AMLs and t(8;21) AMLs in vivo. Thereafter, we will further optimize
370284 by chemical modifications to improve the potency, selectivity, and/or pharmacokinetic parameters. The
ant...

## Key facts

- **NIH application ID:** 10067522
- **Project number:** 5R01CA211614-05
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Jianjun Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $457,310
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067522

## Citation

> US National Institutes of Health, RePORTER application 10067522, Targeting TET1 signaling to treat acute myeloid leukemia (5R01CA211614-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10067522. Licensed CC0.

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