Targeted Degradation of MYB as a Novel Therapeutic Strategy for Acute Myeloid Leukemias

Аннотация

This study examines targeted degradation of SUBMITED 25 June 2025 ACCEPTED 30 June 2025 the transcription factor MYB as a novel therapeutic PUBLISHED 05 July 2025 avenue in acute myeloid leukemias. Its relevance stems VOLUME Vol.07 Issue 07 2025 from the limited efficacy of existing treatment regimens and the emergence of drug‐resistant disease forms. The CITATION work’s novelty lies in the integrated comparison of Oleksandra Bondarenko. (2025). Targeted Degradation of MYB as a Novel Therapeutic Strategy for Acute Myeloid Leukemias. The American Journal genetic models for MYB destabilization, chemical dTAG of Interdisciplinary Innovations and Research, 7(07), 8–15. approaches, and the repurposing of low-molecular- https://doi.org/10.37547/tajiir/Volume07Issue07-02 weight compounds mebendazole and vitaferin A. Data COPYRIGHT © 2025 Original content from this work may be used under the terms are synthesized on MYB’s transformational properties of the creative commons attributes 4.0 License. critical for leukemic-clone maintenance, and experimental findings are reviewed on the suppression of transcriptional programs and induction of blast-cell death following complete factor elimination. Special attention is devoted to prospects for developing PROTAC degraders and molecular glues capable of catalyzing ubiquitin-dependent proteolysis of MYB at low compound doses. The research aims to construct a comprehensive assessment of the efficacy and safety of MYB-degradation strategies and to identify directions for further preclinical investigation. Methods include comparative analysis of peer-reviewed literature, critical appraisal of in vitro and in vivo data, and synthesis of pharmacodynamic profiles of the repurposed agents. The overall evaluation highlights the approach’s potential to overcome therapeutic resistance and improve patient survival. The findings will interest pharmacologists, oncologists, clinical researchers, and specialists in chemical biology. Keywords: acute myeloid leukemia, MYB, proteasomal degradation, PROTAC, mebendazole, vitaferin A, targeted therapy, ubiquitin, molecular glue, drug resistance The American Journal of Interdisciplinary Innovations 8 https://www.theamericanjournals.com/index.php/tajiir and Research INTRODUCTION the scientific findings to date, and to outline prospects for its application. The specific objectives are: Acute myeloid leukemia (AML) remains a challenging disease to cure: escalating chemotherapy regimens no 1. To synthesize data on MYB’s role in AML longer improve outcomes, prompting researchers to pathogenesis and on prior therapeutic attempts focus on selectively suppressing factors that sustain targeting MYB; blast proliferation. The transcription factor MYB, which 2. To describe key experimental governs self-renewal and differentiation of discoveries demonstrating the feasibility of induced hematopoietic stem cells, becomes hyperactivated in MYB degradation and its effects on leukemia; certain contexts—particularly in MLL‐rearranged 3. To discuss the therapeutic potential of leukemias—forming pathogenic expression networks proteasomal‐degradation technologies in comparison that block maturation and drive unchecked growth. In with conventional treatment modalities; experimental models, MYB elimination induces leukemic‐cell death, designating this protein as a high‐ 4. To assess the outlook for integrating priority target for novel therapeutic development. MYB‐degradation approaches into preclinical research and clinical practice. Early intervention strategies aimed to disrupt the MYB– CBP/P300 complex: natural triterpenoids celastrol and plumbagin, alongside synthetic naphthol derivatives, METHODS AND MATERIALS impeded coactivator recruitment, weakened the Z. Anwar [1] delivered a systematic review of degrader transcriptional program, and inhibited blast prospects in leukemia, underscoring the catalytic proliferation. A more radical approach employed the mechanism inherent to the PROTAC approach. M. cell‐penetrating peptidomimetic MYBMIM, designed on Bekesh [2] examined the evolution of the PROTAC the basis of the crystal structure of the interaction platform and its target-selection criteria, identifying interface; MYBMIM displaces MYB from its complex, transcription factors as the most promising candidates. downregulates MYC and BCL2 expression, and triggers K. Klesham [3] experimentally validated the efficacy of apoptosis. In mice bearing human AML xenografts, this vitaferin A in eliminating MYB within AML cell models. T. compound slowed disease progression and extended Harada [4] developed a dTAG system for rapid survival. Despite these encouraging outcomes, MYB degradation of endogenous MYB and assessed the remains present in the nucleus under this strategy, transcriptomic consequences of factor removal. F. limiting the depth of the antitumor effect. Modman [5] described mebendazole’s anti-MYB effects, The concept of induced proteolysis ultimately enables dem