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Huichun Zhan, MD, MS Education/Training:
Clinical interests:
Laboratory interests: 1. Research on the hematopoietic microenvironment (niche) in MPNs Hematopoietic stem cells (HSCs) reside in a specified microenvironment or the “stem cell niche.” Both endothelial cells (ECs) and megakaryocytes (MKs) are important components of the hematopoietic niche. MKs are often located adjacent to marrow sinusoids. Since most HSCs reside close to a marrow sinusoid, the interactions between MKs and the vascular ECs are positioned to play an important role in modulating HSC function. The acquired kinase mutation JAK2V617F plays a central role in MPNs. In addition to mutant blood cells (including MKs), the JAK2V617F mutation is also present in ECs isolated from patients with MPNs. Using murine models that express JAK2V617F specifically in HSCs, MKs, or ECs, we found that: (1) the JAK2V617F mutation can alter the hematopoietic vascular niche function, which not only promotes the mutant stem cell expansion in MPNs but also contributes to the high incidence of disease relapse following allogeneic stem cell transplantation, the only curative treatment for patients with MPNs; (2) the JAK2V617F mutant MKs promote HSC expansion both directly and indirectly through their regulation of the vascular niche. In addition, compared to the non-hematopoietic niche cells, the MK niche provides a mechanism for feedback regulation of HSCs by their own progeny, which is critical for the resilience and function of the hematopoietic system. 2. Research on cell competition in MPNs The HSC compartment in MPN is heterogeneous with the presence of both JAK2 wild-type and JAK2V617F mutant cells in most patients with MPNs. In some patients, there is little or no change in the mutant/wild-type cell ratio over long periods; in others, MPN can evolve into acute leukemia, and patients experience high relapse rates following allogeneic stem cell transplantation, the only curative treatment for these patients. Intrigued by a “negative result” during our study of the MPN vascular niche, we started investigating cell competition in MPNs using in vitro co-culture assays and in vivo competitive transplantation assays. We found that the presence of wild-type cell competition not only alters the gene expression profile and cellular function of JAK2V617F mutant HSCs but also inhibits the expansion of co-existing JAK2V617F mutant cells in a normal microenvironment. Deterioration of the wild-type cell function is associated with MPN disease relapse after stem cell transplantation. In contrast, we found that a diseased vascular niche promotes JAK2V617F mutant HSC expansion over wild-type cells in part due to altered CXCL12/CXCR4 signaling. Therefore, while accumulation of oncogenic mutations is unavoidable during aging, our data suggest that, if we could therapeutically enhance normal cells’ ability to compete, we might be better able to control neoplastic cell expansion and prevent the development of a full-blown malignancy — an active hypothesis being explored in our laboratory. 3. Research on how the JAK2V617F mutation contributes to cardiovascular diseases ~40-50% of patients with MPNs develop arterial or venous thrombosis, with cardiovascular events being the leading cause of morbidity and mortality in these patients. Through an unexpected finding during our study of the vascular niche, we found that the JAK2V617F mutation alters vascular endothelial function to promote a prothrombotic, vasculopathy, and cardiomyopathy phenotype in an MPN murine model. It should be noted that the JAK2V617F mutation is also one of the common mutations associated with clonal hematopoiesis of indeterminate potential (CHIP) and can be detected in ~0.2% individuals of the general population. Individuals with CHIP have a 2-4 fold increase in cardiovascular diseases with worsened clinical outcomes; in particular, individuals with JAK2V617F mutant CHIP have 12 times the risk of cardiovascular events compared to individuals without any CHIP-associated mutations. Therefore, JAK2V617F-positive CHIP and MPNs provide an ideal model system to investigate the relationship between hematopoietic mutations and cardiovascular disorders and have the potential to greatly improve our understanding and treatment of two of the most important human health threats, cancer and heart disease. |
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Lab Personnel: |
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Active Funding Support: |
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Selected Publications:
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Division of Hematology and Oncology
