# Identification of Therapeutic Targets in the Hematopoietic Vascular Niche

> **NIH VA I01** · NORTHPORT VA MEDICAL CENTER · 2020 · —

## Abstract

The myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by stem cell expansion
and overproduction of mature blood cells. The acquired kinase mutation JAK2V617F plays a central role in these
disorders, but the precise molecular mechanisms responsible for MPN stem cell expansion are not fully
understood, limiting the effectiveness of current treatments. Abnormalities of the hematopoietic
microenvironment (niche) are beginning to be recognized as an important factor in the development of
hematologic malignancies including MPNs. Endothelial cells (ECs) are an essential component of the
hematopoietic niche and most hematopoietic stem cells reside adjacent to a marrow sinusoid (the “vascular
niche”). Patients with MPNs are characterized by increased marrow angiogenesis compared to normal marrow
and ECs carrying the JAK2V617F mutation can be detected in these patients. Our recent work demonstrated
that the JAK2V617F-bearing vascular niche not only promotes the expansion of JAK2V617F-mutant stem cells
in preference to JAK2WT stem cells but also protects the mutant cells from lethal irradiation administered during
conditioning for marrow transplantation. The levels of CXCL12, an essential niche factor for stem cell
maintenance and survival, are increased in JAK2V617F-bearing ECs compared to JAK2WT ECs. In addition,
we found that thrombopoietin (TPO) and its receptor MPL, two key regulators of stem cell activity, are also
important for the vascular niche function and MPL is essential for MPN stem cell expansion and the development
of myeloproliferative phenotype in the JAK2V617F-bearing vascular niche. The objective of the proposed work
is to determine the physiological effects and the molecular mechanisms by which the JAK2V617F mutation alters
the hematopoietic vascular niche to promote MPN stem cell expansion. In particular, we propose the following
two specific aims: Aim 1) To test the hypothesis that the JAK2V617F mutation alters vascular niche function to
promote MPN stem cell expansion and disease relapse after stem cell transplantation. The roles of CXCL12 in
JAK2V617F-bearing vascular niche function in MPNs will be determined. In addition, the effects of the
JAK2V617F mutation on human vascular endothelium function will be assessed. Aim 2) To test the hypothesis
that the JAK2V617F mutation changes vascular niche function in MPNs via altered TPO/MPL signaling. The
long term goal of this research proposal is to define the molecular and cellular functions of the hematopoietic
vascular niche in both normal and neoplastic hematopoiesis, and to develop more effective therapeutic strategies
for patients with MPNs and potentially other hematologic malignancies.

## Key facts

- **NIH application ID:** 9664819
- **Project number:** 1I01BX003947-01A2
- **Recipient organization:** NORTHPORT VA MEDICAL CENTER
- **Principal Investigator:** Huichun Zhan
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2019-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9664819

## Citation

> US National Institutes of Health, RePORTER application 9664819, Identification of Therapeutic Targets in the Hematopoietic Vascular Niche (1I01BX003947-01A2). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9664819. Licensed CC0.

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