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June 3rd, 2025
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Huashan Hospital, Fudan University; Center for Cellular and Molecular Diagnostics, Tulane University School of Medicine; Department of Biochemistry and Molecula
cancer biology
biorxiv

Targeting HMGA1-driven leukemic transformation in myeloproliferative neoplasms with pacritinib

Yang, C.Open in Google Scholar•Li, Y.Open in Google Scholar•Chen, K.Open in Google Scholar•Tang, X.Open in Google Scholar•Zhang, Q.Open in Google Scholar•Qin, W.Open in Google Scholar•Fu, J.Open in Google Scholar•Zeng, Y.Open in Google Scholar•Ma, X.Open in Google Scholar•Zheng, W.Open in Google Scholaret al.

Progression of myeloproliferative neoplasms (MPNs) to secondary acute myeloid leukemia (sAML) is a lethal transition lacking reliable early biomarkers and effective therapies. Integrating multi-omics analyses, a cohort of 240 patient biopsies, and functional studies, we identify High Mobility Group A1 (HMGA1) as a critical driver and predictor of this transformation. HMGA1 expression, readily detectable by immunohistochemistry, progressively increases from chronic MPN phases to sAML, outperforming established markers (CD34/CD117) in predicting impending leukemic transformation (AUC = 0.96). Mechanistically, HMGA1 cooperates with JAK2V617F and TP53 mutations to promote leukemogenesis. Clinically, high HMGA1 levels correlate with resistance to first-generation JAK inhibitors and portend poor overall survival. Importantly, the next generation JAK2/FLT3 inhibitor pacritinib abrogates HMGA1-driven proliferation and significantly extends survival in preclinical models, offering an immediate therapeutic strategy for this high-risk population. Our findings establish HMGA1 as an actionable biomarker for risk stratification and early intervention, and a therapeutic target to overcome therapeutic resistance in MPN-sAML.

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