# Targeting DYRK2 to eradicate leukemia stem cells in chronic myeloid leukemia.

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $426,306

## Abstract

Project Summary
Chronic myeloid leukemia (CML) is an aggressive hematological malignancy caused by the oncoprotein
BCRABL1. Although tyrosine kinase inhibitors (TKIs) can help CML patients achieve molecular remission, they
cannot be fully cured because the leukemic stem cells (LSCs) are still present in the body. This application aims
to study a novel actionable mechanism that controls self-renewal and survival in LSCs with the intent to support
the early-stage development of LSC-specific frontline therapy that increases treatment-free remission upon TKI
discontinuation. Our team discovered that the transcription factor KLF4 represses the gene encoding the dual-
specificity tyrosine-phosphorylation regulated kinase DYRK2, allowing LSCs to self-renew and progress the
disease. Thus, deleting the Klf4 gene in a CML mouse model was associated with a lower frequency of LSCs,
leading to leukemia regression and DYRK2 protein upregulation. In addition, inhibiting the SIAH2 ubiquitin ligase
also leads to upregulating the DYRK2 protein, which is associated with cytotoxicity in CML cells. Based on these
findings, we hypothesize that DYRK2 is a critical checkpoint that inhibits the survival and self-renewal in LSCs
that can be activated through genetic and pharmacological stabilization of the DYRK2 protein. In this application,
we propose to investigate the regulation of DYRK2 in CML LSCs through genetic studies to validate this
molecular target and identify DYRK2 stabilizers for drug development. In Specific Aim 1, we propose to study
the mechanism of DYRK2 activation in LSC self-renewal through the phosphorylation of downstream targets. In
Specific Aim 2, we will explore the genetic stabilization of the DYRK2 protein by deleting the gene encoding the
ubiquitin ligase SIAH2 and performing a genome-wide CRISPR/Cas9 screen to identify pathways regulating
DYRK2 expression. In Specific Aim 3, we propose investigating the anti-leukemic properties of pharmacological
stabilization of DYRK2 protein with small molecules identified in a biased approach and cell-based screens in
pre-clinical mouse models as single agents or combined with imatinib. These comprehensive studies will
elucidate how DYRK2 regulates LSCs, how DYRK2 expression is regulated, and what small molecules stabilize
DYRK2 protein for developing LSC-directed therapy in leukemia.

## Key facts

- **NIH application ID:** 10981073
- **Project number:** 1R01CA283079-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Daniel Lacorazza
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $426,306
- **Award type:** 1
- **Project period:** 2024-06-06 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981073

## Citation

> US National Institutes of Health, RePORTER application 10981073, Targeting DYRK2 to eradicate leukemia stem cells in chronic myeloid leukemia. (1R01CA283079-01A1). Retrieved via AI Analytics 2026-06-25 from https://api.ai-analytics.org/grant/nih/10981073. Licensed CC0.

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