Spleen endothelial cells from patients with myelofibrosis harbor the JAK2V617F mutation

Abstract

Increased microvessel density contributes to abnormal BM and spleen microenvironment in myelofibrosis (MF). Taking advantage of the JAK2V617F mutation as a marker of malignancy, in the present study, we investigated whether splenic endothelial cells (ECs) obtained from capillaries by laser microdissection or from fresh spleen tissue by cell culture or cell sorting harbored such mutation in patients bearing the mutation in their granulocytes and undergoing splenectomy for therapeutical reasons. To extend the analysis to the ECs of large vessels, endothelial tissue from the splenic vein was also studied. We found JAK2V617F+ ECs in 12 of 18 patients also bearing the mutation in their granulocytes. In 3 patients, the mutation was found in at least 2 different EC samples obtained by laser microdissection, cell culture, or cell sorting. The mutation was detected in the splenic vein ECs of 1 of 6 patients investigated. In conclusion, we provide evidence that some ECs from the spleen and splenic veins of patients with MF bear the JAK2V617F mutation. We suggest that splenic ECs are involved in the process of malignant transformation in MF.

JAK2V617F-mutant vascular niche contributes to JAK2V617F clonal expansion in myeloproliferative neoplasms

“…15–19 JAK2 V617F mutation is also present in ECs isolated by microdissection from liver and spleen samples of patients with MPNs. 17,20 In addition, we and others have shown that JAK2 V617F ECs are critical in the development of the bleeding abnormalities in a murine model of JAK2 V617F -positive MPNs in which JAK2 V617F is expressed in all hematopoietic cells and endothelial cells. 21 All of these observations suggest that ECs are involved in the pathogenesis of MPNs.…”

“…16,17,20 In addition, ECs are an important niche component of the extramedullary (splenic) hematopoiesis, which is almost always present in patients with MPNs and is associated with MPN disease progression. 13,14 All of these observations suggest that ECs are involved in the malignant process leading to MPNs.…”

Targeted cancer exome sequencing reveals recurrent mutations in myeloproliferative neoplasms

“…Interestingly, endothelial-mesenchymal transition and the resulting endothelial cell fate have been recently implicated in the pathogenesis of PMF. 30, 31, 32 …”

Dysregulation of VEGF-induced proangiogenic Ca2+ oscillations in primary myelofibrosis-derived endothelial colony-forming cells

“…Conversely, VEGF-induced Ca 2þ inflow is remarkably higher in breast cancer-derived ECs than in normal cells [30]. We recently isolated spleen ECs from PMF patients bearing the JAK2 mutation [31]. It will be interesting to assess whether and how the Ca 2þ response to VEGF is altered also in these cells.…”