Targeting HMGA1-driven leukemic transformation in myeloproliferative neoplasms with pacritinib

Yang, C.; Li, Y.; Chen, K.; Tang, X.; Zhang, Q.; Qin, W.; Fu, J.; Zeng, Y.; Ma, X.; Zheng, W.; Huang, Z.; Zhang, W.; Tang, G.; Guan, M.; Wu, Z.

doi:10.1101/2025.06.01.657170

bioRxiv · 10.1101/2025.06.01.657170

Targeting HMGA1-driven leukemic transformation in myeloproliferative neoplasms with pacritinib

Yang, C.·Li, Y.·Chen, K.·Tang, X.·Zhang, Q.·Qin, W.·Fu, J.·Zeng, Y.·Ma, X.·Zheng, W.·Huang, Z.·Zhang, W.·Tang, G.·Guan, M.·Wu, Z.

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Abstract

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. HighlightsO_LIHMGA1 IHC staining serves as a readily implementable biomarker, outperforming existing marker for early prediction of MPN progression to sAML and identifying patients at high risk. C_LIO_LIElevated HMGA1 expression correlates with resistance to first-generation JAK inhibitors and predicts poor overall survival in MPN-sAML patients, highlighting a critical unmet therapeutic need. C_LIO_LIThe next-generation JAK2 inhibitor pacritinib effectively overcomes HMGA1-driven aggressive disease and therapy resistance, offering a rational, clinically available treatment strategy for HMGA1-high MPN-sAML. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/657170v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@18b835org.highwire.dtl.DTLVardef@e5b31dorg.highwire.dtl.DTLVardef@5245caorg.highwire.dtl.DTLVardef@163f5de_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Yang, C., Li, Y., Chen, K., Tang, X., Zhang, Q., Qin, W., Fu, J., Zeng, Y., Ma, X., Zheng, W., Huang, Z., Zhang, W., Tang, G., Guan, M., Wu, Z.. 2025-06-03. Targeting HMGA1-driven leukemic transformation in myeloproliferative neoplasms with pacritinib. https://doi.org/10.1101/2025.06.01.657170

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