Objective:

To investigate the biological and therapeutic significance of BCL-XL in myeloproliferative neoplasms (MPN), focusing on its role in apoptosis resistance and fibrotic progression.

Key Findings:

• BCL-XL was significantly upregulated in JAK2-driven diseases, predominating as the anti-apoptotic protein in malignant hematopoietic cells and fibrotic stromal compartments, indicating its critical role in MPN pathology.
• MPN-derived MSCs exhibited a myofibroblast-like phenotype with increased expression of α-smooth muscle actin and fibronectin, suggesting a shift towards a profibrotic state.
• Inhibition of BCL-XL with ABT-263 induced mitochondrial apoptosis in PMF-derived MSCs and reduced their profibrotic features, highlighting a potential therapeutic avenue.
• TGF-β activated SMAD3 and STAT3 signaling in MSCs, indicating a cooperative engagement of TGF-β/SMAD3 and JAK2/STAT3 pathways in fibrotic activation, which may be targeted for intervention.
• Combined inhibition of BCL-XL and JAK2 produced synergistic antifibrotic and pro-apoptotic effects across various cell types, suggesting a promising strategy for MPN treatment.

Interpretation:

BCL-XL is identified as a key mediator of MPN-associated fibrosis and therapeutic resistance, suggesting that dual targeting of BCL-XL and JAK2 may enhance treatment efficacy and improve patient outcomes in advanced MPN.

Limitations:

• The study primarily focused on patient-derived samples and cell lines, which may not fully represent the complexity of MPN in all patients, potentially limiting the generalizability of the findings.
• On-target thrombocytopenia remains a challenge due to the physiological role of BCL-XL in platelets, necessitating careful consideration in therapeutic applications.

Conclusion:

The findings highlight the dual role of BCL-XL in promoting leukemia cell survival and sustaining stromal fibrosis, supporting the rationale for targeting BCL-XL in MPN therapy and suggesting further exploration of this approach in clinical settings.