Open Access

REVIEW

Transcriptional Control as a Therapeutic Strategy in Acute Myeloid Leukemia

Annisa Nurul Ilmi¹, Rudy Agung Nugroho¹, Sendy Junedi², Hiroki Goto^3,*
1 Department of Biology, Faculty of Mathematics and Natural Sciences, Mulawarman University, Samarinda, Indonesia
2 Faculty of Biotechnology, Universitas Atma Jaya Yogyakarta, Yogyakarta, Indonesia
3 Division of Radioisotope and Tumor Pathobiology, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan
* Corresponding Author: Hiroki Goto. Email:
(This article belongs to the Special Issue: Molecular Targeting Therapy for Anticancer Treatment)

Oncology Research https://doi.org/10.32604/or.2026.083351

Received 02 April 2026; Accepted 16 July 2026; Published online 17 August 2026

Abstract

Acute myeloid leukemia (AML) is driven by dysregulated transcription factors (TFs) that disrupt hematopoietic differentiation, promote leukemic self-renewal, and confer therapy resistance. Key TFs including C/EBPα, PU.1, RUNX1, GATA2, EVI1, PML-RARα fusion protein, p53, c-Myc and ERG are altered through mutations, chromosomal rearrangements, and epigenetic remodeling, rewiring transcriptional circuits that converge on oncogenic pathways such as Wnt/β-catenin, NF-κB, and JAK/STAT3. Although TFs were historically considered “undruggable” due to their flat protein–protein interaction interfaces and lack of enzymatic pockets, recent advances have increasingly demonstrated their clinical tractability. The menin inhibitors revumenib and ziftomenib, which disrupt the Menin–KMT2A complex to suppress HOXA/MEIS1-driven transcription, have received FDA approval for relapsed or refractory NPM1-mutant AML, with revumenib also approved for KMT2A-rearranged acute leukemia. While these agents target a transcriptional regulatory complex rather than TFs directly, their clinical success highlights the therapeutic potential of modulating transcriptional regulatory networks and encourages the development of future therapies targeting TFs and their associated regulatory machinery. Additional strategies include reactivation of tumor suppressor pathways through p53-targeting agents, disruption of aberrant CBFβ–RUNX1 signaling, inhibition of FOXM1 and NF-κB, and epigenetic modulation through DOT1L, LSD1, and HDAC inhibitors. Emerging technologies are further expanding the druggable space: PROTACs and molecular glues enable event-driven degradation of previously intractable targets such as TAF1 and GSPT1, while artificial intelligence and graph-based machine learning facilitate identification of novel TF cascade vulnerabilities. However, durable clinical translation remains constrained by acquired resistance through MEN1 mutations and p300-mediated transcriptional remodeling, off-target hematopoietic toxicity, differentiation syndrome, transcriptional plasticity, and delivery challenges within the bone marrow microenvironment. This review provides a comprehensive synthesis of TF dysregulation mechanisms, genotype-specific targeting strategies linking molecular subtype to therapeutic approach, clinical trial outcomes, and emerging drug design technologies, offering a translational framework to guide the development of next-generation TF-targeted therapies in AML.

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Keywords

Acute myeloid leukemia (AML); transcription factors (TFs); transcriptional dysregulation; small molecules

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