{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:38:59Z","timestamp":1788914339073,"version":"build-2803163510"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Myeloproliferative neoplasms (MPNs) are frequently accompanied by bone marrow fibrosis and leukemic transformation, yet the cellular and molecular mechanisms that sustain apoptosis resistance and fibrotic progression remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Bone marrow mesenchymal stromal cells (BM-MSCs) from patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) were analyzed for fibrotic phenotype, apoptosis signaling, and pathway activation using cell counting kit-8, immunofluorescence, flow cytometry, western blotting, hydroxyproline and transmission electron microscopy. The cytotoxic and antifibrotic effects of the BCL-XL inhibitor ABT-263 (navitoclax), alone or combined with the JAK2 inhibitor ruxolitinib, were evaluated in stromal and hematopoietic contexts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>BCL-XL was markedly upregulated in JAK2-driven disease and predominated over other BCL-2 family members in both malignant hematopoietic cells and fibrotic stromal compartments. MSCs derived from MPN patients exhibited a myofibroblast-like phenotype characterized by increased \u03b1-smooth muscle actin (\u03b1-SMA) and fibronectin (FN) expression. Pharmacologic inhibition of BCL-XL with ABT-263 selectively induced mitochondrial apoptosis in PMF-derived MSCs and attenuated their profibrotic features. Mechanistically, transforming growth factor \u03b2 (TGF-\u03b2) activated both SMAD3 and STAT3 signaling in MSCs, indicating cooperative engagement of TGF-\u03b2\/SMAD3 and JAK2\/STAT3 pathways in stromal fibrotic activation. Combined inhibition of BCL-XL and JAK2 produced synergistic antifibrotic and pro-apoptotic effects in MSCs, post-MPN acute myeloid leukemia (AML) cell lines, and patient-derived cells resistant to ruxolitinib.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Collectively, these findings identified BCL-XL as a key mediator of MPN-associated fibrosis and therapeutic resistance, and confirmed dual targeting of BCL-XL and JAK2 as a rational strategy for advanced MPN.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1818806","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:42:13Z","timestamp":1780378933000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["BCL-XL drives fibrotic and leukemic progression in myeloproliferative neoplasms"],"prefix":"10.3389","volume":"17","author":[{"given":"Chunyan","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Hematology, Fujian Medical University Union Hospital, Fujian Medical University","place":["Fuzhou, Fujian, China"]},{"name":"Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital","place":["Fuzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiting","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Fujian Medical University Union Hospital, Fujian Medical University","place":["Fuzhou, Fujian, China"]},{"name":"Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital","place":["Fuzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanchao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Fujian Medical University Union Hospital, Fujian Medical University","place":["Fuzhou, Fujian, China"]},{"name":"Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital","place":["Fuzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hematology, Fujian Medical University Union Hospital, Fujian Medical University","place":["Fuzhou, Fujian, China"]},{"name":"Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital","place":["Fuzhou, Fujian, China"]},{"name":"Department of Hematology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi Medical 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