BCL-XL inhibition with ABT-263 and ruxolitinib synergistically targets myeloproliferative neoplasm fibrosis and leukemic cells.

Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are characterized by uncontrolled hematopoietic cell proliferation often leading to debilitating bone marrow fibrosis and a high risk of leukemic transformation. Current therapies, such as JAK2 inhibitors like ruxolitinib, can manage symptoms but often fail to halt disease progression or prevent transformation, particularly in advanced stages. A critical gap exists in understanding the molecular mechanisms driving apoptosis resistance and fibrotic progression, which are key to developing more effective treatments for these aggressive blood cancers.

Researchers investigated the role of BCL-XL in MPN progression using bone marrow mesenchymal stromal cells (BM-MSCs) derived from patients with PV, ET, and PMF, alongside post-MPN acute myeloid leukemia (AML) cell lines. They analyzed fibrotic phenotype, apoptosis signaling, and pathway activation using cell counting kit-8, immunofluorescence, flow cytometry, western blotting, hydroxyproline assays, 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 these stromal and hematopoietic contexts to assess their therapeutic potential.

BCL-XL was markedly upregulated in JAK2-driven disease, dominating over other BCL-2 family members in both malignant hematopoietic cells and fibrotic stromal compartments. MSCs from MPN patients displayed 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 AML cell lines, and patient-derived cells resistant to ruxolitinib, highlighting a potent therapeutic strategy.