Biophysical mechanisms underlying the tumor-suppressive functions of myeloid transcription factors in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by impaired myeloid differentiation and uncontrolled proliferation. Central to its pathogenesis is the dysfunction of transcription factors that normally maintain hematopoietic homeostasis by directing lineage commitment and restricting cell growth. Although the genetic and epigenetic alterations that affect these factors have been extensively characterized, the biophysical mechanisms underlying their contribution to leukemogenesis remain incompletely understood. This review integrates insights from structural biology, chromatin profiling, transcriptome analyses, and pharmacological studies to delineate the biophysical principles by which key myeloid transcription factors-PU.1, IRF8, CEBPA, RUNX1, and GFI1-exert tumor-suppressive functions. We focus on how sequence-specific DNA recognition, cooperative complex assembly, chromatin accessibility, and dynamic protein–protein interactions govern transcriptional regulation in both normal and leukemic hematopoiesis. Disruption of these transcription factor networks may arise from mutations that alter the DNA-binding affinity, isoform switching that reshapes cofactor interactions, or the formation of aberrantly repressive complexes. These alterations converge on transcriptional reprogramming that favors proliferation over differentiation. Notably, the biophysical interfaces which mediate these interactions, such as the SNAG domain–lysine-specific demethylase 1 (LSD1) axis in GFI1, represent promising targets for therapeutic intervention. Elucidating these molecular mechanisms provides a framework to understand the disease heterogeneity and to develop differentiation-based therapies in AML.

Keywords

acute myeloid leukemia / transcription factors / hematopoietic differentiation / chromatin remodeling / epigenetic regulation

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