# Dissecting the canonical and non-canonical functions of Tet2 in hematopoietic stem cells and hematologic disorders

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2022 · $694,860

## Abstract

ABSTRACT
Myelodysplastic syndromes (MDS) comprise a group of clonal hematologic malignancies characterized by
ineffective hematopoiesis coupled with morphologic dysplasia, and generally remains incurable by existing non-
transplant therapy. The Ten-eleven translocation (TET) proteins constitute a family of enzymes that assure
proper regulation of gene expression through DNA demethylation, and TET2 is one of the most frequently
mutated genes in MDS. Tet2’s roles in hematopoiesis have largely been studied in knockout mice; Tet2 deletion
causes progressive defects in hematopoiesis, including the aberrant self-renewal of hematopoietic stem cells
(HSCs), and Tet2-deficient mice develop a chronic myelomonocytic leukemia-like disease. However, as these
mice lack the entire protein, it is not known how the non-catalytic functions of Tet2 contribute to HSC function
and MDS pathogenesis. In order to delineate the catalytic and non-catalytic functions of Tet2, we have
established Tet2 catalytically inactive mice. Using this new genetic mouse model, we have obtained the
compelling evidence that Tet2 catalytic mutant mice have less pronounced hematologic phenotypes than Tet2
knockout mice. These preliminary findings led us to hypothesize that, in addition to its enzymatic roles in DNA
hydroxylation/demethylation, Tet2 is critical for the proper governance of HSCs and suppression of MDS in a
catalytic-independent manner. In this study, we will conduct a comparative epigenomic, transcriptomic and
hematologic analyses of Tet2 catalytic mutant and knockout mice to establish the non-catalytic requirements of
Tet2 in HSC homeostasis and MDS suppression. We have three main goals: (1) to determine the contributions
of non-catalytic Tet2 functions to HSC self-renewal and differentiation, (2) to define the suppressive roles of non-
catalytic functions of Tet2 in loss-of-Tet2-driven MDS, and (3) to identify non-catalytic targets of Tet2 responsible
for suppressing aberrant HSC homeostasis and MDS development. The proposed research will have a major
impact on the MDS field by defining the contribution of the non-catalytic functions of TET2 to MDS etiology, and
can lead to new therapeutic approaches for the treatment and management of MDS and other hematologic
disorders.

## Key facts

- **NIH application ID:** 10427353
- **Project number:** 5R01HL148852-04
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Meelad Dawlaty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $694,860
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427353

## Citation

> US National Institutes of Health, RePORTER application 10427353, Dissecting the canonical and non-canonical functions of Tet2 in hematopoietic stem cells and hematologic disorders (5R01HL148852-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10427353. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*