# NIH grant: Project 3 - Non-cell-intrinsic mechanisms of JAK2-mutant HSC clonal expansion (1P01HL185367-01) — retained record

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NIH grant 1P01HL185367-01: Project 3 - Non-cell-intrinsic mechanisms of JAK2-mutant HSC clonal expansion
Institute: {'code': 'HL', 'abbreviation': 'NHLBI', 'name': 'National Heart Lung and Blood Institute', 'admin_org_id': '12500068', 'admin_funding_url': ''}. PI: Daniel C Link. Award: $544250.
Start: 2026-08-15T00:00:00.
PROJECT SUMMARY – PROJECT 3 (Link)
The central hypothesis of this project is that changes in the bone marrow microenvironment play a key role in
the evolution of JAK2-mutant MPNs. The bone marrow microenvironment contains a rich network of
phenotypically and functionally heterogeneous stromal cells that provide key signals that maintain
hematopoietic stem/progenitor cells (HSPCs). Our single cell-RNA sequencing and spatial transcriptomic data
show that there is a marked decrease in LEPR+ stromal cells in human MPN This loss of LEPR+ cells is
associated with decreased CXCL12 and kit ligand expression, niche disruption, and the development of
extramedullary hematopoiesis. However, the signals that target LEPR+ cells are not well understood. We have
generated preliminary data supporting the hypothesis that both TGF-β and TNF-α contribute to
hematopoietic niche disruption in MPNs by decreasing CXCL12 and kit ligand expression in LEPR+
cells. Megakaryocyte hyperplasia is a hallmark feature of MPNs. Megakaryocytes are a key component of the
stem cell niche in the bone marrow, producing several factors that regulate HSPCs and stromal cells, including
TGF-β. Our preliminary data have established the importance of TGF-β signaling in HSCs for clonal expansion
of Jak2V617F HSCs. Preliminary spatial transcriptomics data show that human JAK2V617F MPN is associated with
distinct megakaryocyte clusters, containing both mature and immature megakaryocytes. Together, these
observations suggest the hypothesis that JAK2V617F megakaryocytes play a key early step in the
pathogenesis of MPNs through expression of TGF-β and other mediators that induce alterations in the
local microenvironment that, in turn, favor expansion of JAK2V617F HSCs. Three Aims are proposed: 1)
Determine whether TNF-α alone or in combination with TGF-β contributes to stem cell niche disruption in
MPNs.; 2) Determine whether TGF-β expression in megakaryocytes is required for the clonal expansion of
Jak2V617F HSCs; and 3) Characterize alterations in the cellular microenvironment induced by JAK2-mutant
megakaryocytes. These studies will advance our understanding of mechanisms of hematopoietic niche
disruption in MPNs and its impact on MPN phenotype and clonal progression. It will provide new insight into
the roles of TGF-β and TNF-α in the regulation of LEPR+ cell number and function, which will have implications
for other inflammatory conditions. Finally, these data will provide new insight into the role of megakaryocytes
in organizing the stem cell niche.
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