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This research evaluates the efficacy and mechanisms of JAK2 inhibitors in myeloproliferative neoplasms.

April 5, 2026

Abstract 7536: In vitro and in vivo screening platform for discovery of JAK2 inhibitors

Key Points

This research evaluates the efficacy and mechanisms of JAK2 inhibitors in myeloproliferative neoplasms.
Established a murine model of JAK2-driven disease through cell line transplantation.
Monitored disease progression using bioluminescent imaging.
Conducted terminal analyses for splenomegaly, serum biochemistry, and histopathology.
Tested cell lines with varying concentrations of JAK2 inhibitors including Ruxolitinib, Fedratinib, and Tofacitinib.
Quantified inhibition of JAK2-STAT5 signaling and calculated IC50 values.
Mice exhibited splenomegaly, decreased survival, and elevated serum ALT/AST levels.
Ruxolitinib significantly reduced tumor burden and extended survival.
Differential sensitivity to JAK2 inhibitors was observed across cell lines.

Abstract

Abstract Background: The JAK-STAT signaling pathway, activated by cytokine receptors, plays a central role in regulating cell proliferation, differentiation, apoptosis, and immune responses. JAK2, a key kinase in this pathway, transduces signals from hematopoietic growth factor receptors such as thrombopoietin (TPO), erythropoietin (EPO), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Dysregulation of JAK2 is implicated in the pathogenesis of myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), myelofibrosis (MF), and essential thrombocythemia (ET). Objectives: This study aimed to evaluate the efficacy of JAK2 inhibitors, elucidate their mechanisms of action, and identify optimal dosing strategies to maximize therapeutic benefit while minimizing adverse effects. Method: An In vivo, a murine model of JAK2-driven myeloproliferative disease was established by intravenous transplantation of JAK2-activated cell lines into BALB/c nude mice. Disease progression was monitored using bioluminescent imaging. Terminal analyses included evaluation of splenomegaly, serum biochemistry (ALT and AST), and splenic histopathology (hematoxylin and eosin staining).For in vitro analysis, a panel of cell lines was treated with increasing concentrations of JAK inhibitors (Ruxolitinib, Fedratinib, and Tofacitinib) to evaluate compound efficacy. Inhibition of downstream JAK2-STAT5 signaling was quantified using an α-LISA for phosphorylated STAT5 (p-STAT5). Dose-response profiles were generated, and IC50 values were calculated to determine the relative sensitivity of the cells to each agent. Results: In vivo, our model mice displayed progressive increases in bioluminescent signal, marked splenomegaly and hepatomegaly, decreased survival, and elevated serum ALT/AST levels. Ruxolitinib treatment significantly suppressed bioluminescent signal progression, reduced hepatic and splenic tumor burden, and extended survival.In vitro, Ruxolitinib potently and dose-dependently inhibited JAK2-STAT5 signaling, with IC50 values confirming target sensitivity. The cell lines exhibited differential sensitivity to the JAK2 inhibitors Ruxolitinib, Fedratinib, and Tofacitinib. Conclusion: We established integrated in vivo and in vitro screening platforms for the discovery and evaluation JAK2 inhibitors. This model provides a valuable tool for optimizing treatment regimens against JAK2-driven pathologies. Citation Format: Na Li, Hao Huang, Xinyu Zhong, Guoqian Wang, Xuyang Duan, Yue Huang, Jinying Ning, Feng Hao, . In vitro and in vivo screening platform for discovery of JAK2 inhibitors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7536.

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