Pathogenic Mechanisms of Systemic Mastocytosis: Unraveling the Genetic Complexity, Bone Marrow Microenvironment, and...

Systemic mastocytosis (SM) was historically classified as a myeloproliferative neoplasm, but it was redefined in 2016 as a distinct entity in the World Health Organization classification. Characterized by abnormal mast cell (MC) proliferation, SM can present as a cutaneous form or as a systemic disease involving multiple organs. It spans a spectrum from indolent forms with an excellent prognosis to more aggressive variants associated with organ dysfunction and life-threatening complications. The most significant molecular discovery in SM is the presence of mutations in the KIT gene, particularly D816V, which plays a pivotal role in disease progression. Additional mutations in genes such as SRSF2, ASXL1, and TET2 have been identified, contributing to the genetic complexity of SM and influencing clinical outcomes. The bone marrow microenvironment plays a critical role in the pathogenesis of SM, serving as the primary site for MC proliferation and influencing disease progression through interactions with various cellular components. This review highlights the importance of the bone marrow microenvironment in sustaining abnormal MC proliferation and activation, providing insights into potential therapeutic strategies targeting these interactions. We also explore the genetic and molecular mechanisms involved, underscoring their diagnostic and therapeutic implications.