JAK2V617F Mutated Endothelium Has a Stem Cell Potential in Primary Myelofibrosis: a New Disease Ontogenesis for Chronic Myeloproliferative Disorders
Key claim: JAK2V617F-mutated endothelial cells in primary myelofibrosis may represent embryonic-like hemogenic endothelium with multilineage clonogenic potential, suggesting they constitute the malignant stem cell pool and cell of origin for PMF.
Abstract
The present project aims to experimentally test the hypothesis that JAK2V617F mutated endothelium in primary myelofibrosis (PMF) we discovered in 2013 represents an embryonic-like hemogenic endothelium and is part of the malignant stem cell pool that give rise to clonal hematopoiesis. The hypothesis stems from the recent evidence that JAK2 mutation in PMF patients is acquired in utero or childhood. The experimental plan of the project is 1) to separate mature endothelial cells from peripheral blood of PMF patients for morphological, molecular, functional characterization and clonogenic assays; 2) to assay the megakaryocyte, erythroid, granulocyte and endothelial clonogenic potential of the mature endothelial cells of patients with PMF. The potential to form colonies will be the documentation that a fraction of mature endothelial cells of patients with PMF have the characteristics of embryonic hemogenic endothelium and might act as the cell of origin of PMF.
Why this matters
If JAK2V617F-mutated endothelium acts as a hemogenic, stem-cell-like compartment in PMF, the disease ontogenesis of PMF diverges fundamentally from the canonical HSC-centric model shared across MPN subtypes, with direct implications for why fibrosis and extramedullary hematopoiesis dominate PMF natural history versus ET/PV. It also reframes transplant logic and minimal residual disease tracking for PMF, since eradicating HSC-derived clones would be insufficient if the endothelial niche itself is the reservoir. This is a subtype-defining mechanistic hypothesis warranting prospective contrast with ET and PV, where endothelial JAK2V617F has been documented but a hemogenic role has not been claimed.