From skull to brain: The pathophysiology of myeloproliferative neoplasm
Myeloproliferative neoplasms (MPNs) are chronic blood cancers arising from somatically mutated hematopoietic stem cells (HSCs). MPN pathogenesis involves clonal expansion of mutant HSCs and uncontrolled myelopoiesis, accompanied by aberrant cytokine and chemokine signaling and progressive bone marrow (BM) remodeling. Regardless of the MPN subtype, the majority of patients have significantly reduced quality of life (QoL) due to high symptom burden and disease-associated complications. Complaints like fatigue, sleep and vision disturbances, concentration problems, and strokes, indicate that MPNs also impact the central nervous system (CNS). Recently, insights into CNS immunity revealed that the skull harbors a unique BM niche that supplies immune cells to the healthy and diseased brain and its supporting structures, such as the meninges. While the effects of disease manifestation on common hematopoietic sites like the femur and spleen are well established, the impact of MPN on cranial hematopoiesis and CNS homeostasis remains poorly defined.
We employed a thrombopoietin (ThPO)-induced murine model of MPN to investigate hematopoietic and stromal remodeling in the skull BM, dura mater, and brain. Flow cytometry, immunohistochemistry, and multiplex immunoassays were used to characterize changes in hematopoietic composition, stromal niche remodeling, and inflammatory signaling.
MPN mice exhibited robust expansion of hematopoietic stem and progenitor cells (HSPCs) in the skull BM, including multipotent progenitors, common myeloid progenitors, and megakaryocyte-erythroid progenitors. This was accompanied by skewing toward granulocytic, monocytic, and megakaryocytic lineages, with a concomitant reduction in lymphoid cells. Histological analysis confirmed engraftment of donor-derived HSCs and revealed aberrant megakaryopoiesis, myelofibrosis, and stromal cell activation (α-SMA+, FAP+) within the cranial niche.
Given the anatomical continuity between skull BM and dura mater via newly discovered ossified channels, we next evaluated dural tissues. ThPO mice exhibited increased infiltration of granulocytes and monocytes, and a marked reduction in B cells. Multiplex cytokine analysis of the meninges showed elevated levels of key pro-inflammatory cytokines, such as IL-1α, TNF-α, and IL-6 in ThPO mice. The dura also exhibited increased vascularization, stromal activation, and rare fibrotic lesions, indicating MPN-driven remodeling beyond the BM compartment.
Remarkably, inflammatory cytokines were also elevated in brain lysates. Immunohistochemical analysis detected mutated hematopoietic cells within the cortex, pia mater, and ventricles, suggesting CNS infiltration and MPN-driven neuroinflammation. Brain weights were modestly increased, but no overt neurodegeneration was observed.
These findings identify the skull BM and dura mater as previously underrecognized sites of MPN-driven pathology. MPNs promote myeloid-biased hematopoiesis, fibrotic niche remodeling, and local immune dysregulation in the cranial compartments, with downstream neuroinflammatory consequences and cell infiltration into the CNS. This cranial axis of disease may contribute to the CNS-related symptoms in MPN patients and their poor QoL, and represents a novel avenue for therapeutic intervention.