title: JAK2V617F-mutant vascular niche contributes to JAK2V617Fclonal expansion in myeloproliferative neoplasms.
abstract: The myeloproliferative neoplasms (MPNs) are characterized by hematopoietic stem/progenitor cell (HSPC) expansion and overproduction of blood cells. The acquired mutation JAK2V617Fplays a central role in these disorders. Mechanisms responsible for MPN HSPC expansion is not fully understood, limiting the effectiveness of current treatments. Endothelial cells (ECs) carrying the JAK2V617Fmutation can be detected in patients with MPNs, suggesting that ECs are involved in the pathogenesis of MPNs. Here we report that JAK2V617F-bearing primary murine ECs have increased cell proliferation and angiogenesis in vitro compared to JAK2WTECs. While there was no difference between JAK2V617Fand JAK2WTHSPC proliferation when co-cultured with JAK2WTEC, the JAK2V617FHSPC displayed a relative growth advantage over the JAK2WTHSPC when co-cultured on JAK2V617FEC. In addition, the thrombopoietin (TPO) receptor MPL is up regulated in JAK2V617FECs and contributes to the maintenance/expansion of the JAK2V617Fclone over JAK2WTclone in vitro. Considering that ECs are an essential component of the hematopoietic niche and most HSPCs reside in the perivascular niche, our studies suggest that the JAK2V617F-bearing ECs form an important component of the MPN vascular niche and contribute to mutant stem/progenitor cell expansion, likely through a critical role of the TPO/MPL signaling axis.
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Chi Hua Sarah
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Office of the Sr. Vice President, Health Sciences, Stony Brook Medicine, NY, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kaushansky
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Stony Brook University, Stony Brook, NY, USA; Northport VA Medical Center, Northport, NY, USA. Electronic address: Huichun.Zhan@stonybrookmedicine.edu.
authors.forename: Huichun
authors.initials: H
authors.lastname: Zhan
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics*; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000473:pathology; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D051379:Mice; D020125:Mutation, Missense; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D009369:Neoplasms / Q000235:genetics; D009389:Neovascularization, Pathologic; D053628:Receptors, Thrombopoietin / Q000378:metabolism / Q000502:physiology*; D055153:Stem Cell Niche
chemical_list: D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: Endothelial cells; Hematopoietic stem/progenitor cells; JAK2(V617F); MPL; Microenvironment; Myeloproliferative neoplasms