# A Novel E3 Ubiquitin Ligase for CML Stem Cells

> **NIH NIH R21** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2020 · $188,138

## Abstract

Project Summary
Chronic myeloid leukemia (CML) is a lethal malignancy. Today, tyrosine kinase inhibitors (TKIs) effectively
treat the disease, leading to rapid expansion of long-term CML survivors. However, TKIs fail to eradicate CML
leukemia stem cells (LSCs) and the disease relapses when the drug is stopped. As a result, CML patients
need life-long dependence on TKIs. There is a need to eradicate CML LSCs for a cure. Our long-term goal is
to understand the mechanisms of CML LSC drug resistance, and to develop novel strategies to eradicate CML
LSCs and improve CML treatment. We have previously shown that protein deacetylase SIRT1 is activated by
BCR-ABL transformation and promotes CML progression and LSC drug resistance. In our recent study of
hematopoietic stem cell (HSC) aging, we identified an E3 ubiquitin ligase Trim26 as a novel Sirt1 effector in old
mouse HSCs. We found that Trim26 inhibition had strikingly similar effect to SIRT1 inhibition on suppressing
CML cell growth and survival. Trim26 was over-expressed in both human and mouse CML progenitor cells,
and Trim26 knockout reduced CML LSCs. Unlike Sirt1 knockout, Trim26 knockout did not affect normal mouse
development and functions. The objective of this application is to determine the roles of Trim26 in regulating
CML LSC survival and self-renewal. Our central hypothesis is that Trim26 promotes CML LSC survival and
maintenance and facilitates leukemia development. The rationale for the proposed research is that better
understanding the roles of Trim26 in CML LSCs will help design a more effective and safer strategy to
eradicate CML LSCs and bring a cure to the disease. We will test our central hypothesis in two specific aims:
1) To determine the role of Trim26 in CML LSC survival and self-renewal; 2) To determine the mechanisms of
Trim26 in regulating CML LSCs. Under aim 1, the effect of Trim26 knockout on CML LSC survival and
maintenance as well as the LSC persistence upon TKI treatment will be determined using a mouse model of
CML. Under aim 2, the requirement of Trim26 E3 ubiquitin ligase activity for LSC functions and CML
development, and novel ubiquitination substrates of Trim26 will be determined for regulation of CML LSC
functions and leukemia development. The proposed research is significant because it will reveal a new
mechanism of CML LSC survival and drug resistance, and identify Trim26 as a novel and safe therapeutic
target to eradicate CML LSCs.

## Key facts

- **NIH application ID:** 9932933
- **Project number:** 5R21CA229967-02
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** WENYONG CHEN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $188,138
- **Award type:** 5
- **Project period:** 2019-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932933

## Citation

> US National Institutes of Health, RePORTER application 9932933, A Novel E3 Ubiquitin Ligase for CML Stem Cells (5R21CA229967-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9932933. Licensed CC0.

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