Super‐Enhancer‐Driven SOX4/SMAD3 Mediate Membrane Remodeling by Regulating Phospholipid Metabolism to Accelerate Leukemia Progression

ABSTRACT Chronic myeloid leukemia (CML) is driven by the BCR‐ABL fusion oncogene and progresses from chronic phase (CP) to blast phase (BP). While tyrosine kinase inhibitors (TKIs) effectively control CML‐CP, CML‐BP remains a therapeutic challenge characterized by treatment resistance and poor survival. Accumulating evidence indicates that aberrant activation of epigenetic regulatory elements remodels the transcriptome in cancer, creating dependencies on specific transcriptional regulators that drive cancer progression. However, whether specific transcriptional mechanisms promote the transition from CML‐CP to CML‐BP remains unclear. This study identifies super‐enhancer‐driven transcription factors SOX4 and SMAD3 in CML‐BP. SOX4 and SMAD3 engage in a positive feedback axis through mutual binding to their respective super‐enhancers and promoters. Functional assays confirm that this axis promotes leukemic progression in vitro and in vivo. Mechanistically, SOX4/SMAD3 bind to the promoter and enhancer regions of the receptor tyrosine kinase AXL, enhancing its transcription and subsequently activating the AKT/ERK/STAT5 signaling. Concurrently, they transcriptionally upregulate LPCAT1, which remodels membrane phospholipids to facilitate AXL localization. Notably, the AXL inhibitor Bemcentinib effectively suppressed CML‐BP progression in both in vivo and in vitro models. Collectively, our findings establish SE‐driven SOX4 and SMAD3 as key regulators in CML‐BP and identify Bemcentinib as a promising therapeutic strategy.