BRIEF RESEARCH REPORT article
Front. Oncol.
Sec. Hematologic Malignancies
This article is part of the Research TopicCombination Therapies in Acute Myeloid Leukemia (AML)View all 7 articles
TLK2 antisense oligonucleotide as a new strategy to target TLK2 in acute myeloid leukemia
Provisionally accepted
Anupriya Agarwal1*
Hsin-Yun Lin1
Sokchea Khou1
Evan F Lind1Katia G. de Oliveira Rebola1Ariel Dean1
Angelica Tolentino2Hadi Maazi2Alexey Revenko2- 1Oregon Health and Science University, Portland, United States
- 2Ionis Pharmaceuticals Inc, Carlsbad, United States
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Abstract Introduction: Tousled-like kinase 2 (TLK2) is a serine/threonine kinase that plays a role in DNA replication, chromatin remodeling, and DNA damage response. TLK2 has been implicated in the pathogenesis of various types of cancer, including breast cancer, glioblastoma, and acute myeloid leukemia (AML). However, no potent and selective TLK2 inhibitors have been developed. Methods: We evaluated the efficacy of a human TLK2 antisense oligonucleotide (ASO) alone and in combination with gilteritinib in AML cell lines. To assess vivo efficacy and toxicity, we administered a mouse TLK2 ASO alone or in combination with gilteritinib in a murine model of AML. Results: TLK2 ASO treatment resulted in a dose-dependent reduction of TLK2 mRNA levels and decreased cell viability in FLT3-mutant AML cell lines, with enhanced cytotoxicity observed when combined with gilteritinib. In a murine AML model, TLK2 ASO achieved approximately 50% knockdown efficiency. Both TLK2 ASO alone and in combination with gilteritinib significantly reduced spleen size, leukemia burden, and bone marrow progenitor cell populations. The treatment was generally well tolerated, with only minimal toxicity observed. Discussion: This study demonstrates that TLK2 ASO is a promising therapeutic strategy for AML, particularly in combination with FLT3 inhibition, and may apply to other TLK2-driven cancers. Future efforts should focus on improving ASO delivery and knockdown efficiency to maximize therapeutic benefit.
Keywords: AML, Antisense oligonucleotide, Drug Resistance, Gilteritinib, Tlk2
Received: 03 Jul 2025; Accepted: 04 Feb 2026.
Copyright: © 2026 Agarwal, Lin, Khou, Lind, G. de Oliveira Rebola, Dean, Tolentino, Maazi and Revenko. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Anupriya Agarwal
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