Dissecting Bone Marrow Fibrosis in Philadelphia-Negative Myeloproliferative Neoplasms: Multiple Roads Lead to Rome

Philadelphia-negative myeloproliferative neoplasms (MPN), a spectrum of blood malignancies characterized by uncontrolled myeloid proliferation, persist as a key challenge in onco-hematology due to their intricate molecular background, heterogeneous clinical phenotypes, and variable prognoses. Although generally accepted as indolent disorders, a considerable fraction of MPN patients exhibit progressive, and sometimes accelerated, bone marrow fibrosis, reflecting a critical shift toward a more debilitating condition marked by an increased symptom burden. As marrow scarring advances, hematopoietic capacity declines, severely compromising both patients' quality of life and survival. Increasing evidence highlights the crucial involvement of multiple players and mechanisms orchestrating marrow fibrotic transformation, thereby reflecting the multifaceted nature of this pathogenetic process. In this review, we untangle the pro-fibrotic programs underlying fibrosis progression in MPN, critically analyzing the available scientific literature. We explore the potential impact of the mutational landscape on the fibrotic transformation risk and examine the role of dysfunctional megakaryocytes as principal catalysts of fibrotic remodeling. Additionally, we provide insight into the influence of the bone marrow microenvironment, examining the contribution of both soluble factors and direct cell-cell communication in sustaining and exacerbating the fibrotic signature. The urgent need for earlier diagnoses, tailored prognoses, and more effective therapeutic strategies stresses the importance of investigating the pathological basis of fibrotic progression from a deeper perspective.