BCL-XL drives fibrotic and leukemic progression in myeloproliferative neoplasms

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.

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.

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 α-smooth muscle actin (α-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 β (TGF-β) activated both SMAD3 and STAT3 signaling in MSCs, indicating cooperative engagement of TGF-β/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.

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.