Huichun Zhan, MD, MSHuichun Zhan, MD, MS
Attending Physician, Northport VA Medical Center
Associate Professor, Stony Brook University
Email: Huichun.zhan@stonybrookmedicine.edu
Lab Location: Health Sciences Tower, 15th Floor,  Room 89


Education/Training:

  • Hematology-oncology fellowship, The Johns Hopkins University School of Medicine
  • Internal Medicine, Albert Einstein College of Medicine at Long Island Jewish Medical Center
  • M.D., Peking Union Medical College, Beijing, China
  • M.S., Cornell University Weill Graduate School of Medical Sciences, New York, NY

Clinical interests:

  • Polycythemia vera
  • Essential thrombocythemia
  • Primary myelofibrosis
  • Bleeding
  • Thrombosis
  • Clonal hematopoiesis and cardiovascular diseases

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.

 


Lab Personnel:

Sandy Lee, Graduate Student (Pharmacology)
Haotian Zhang, Graduate student (Molecular Cellular Biology)
Nicholas Kafeiti, Technician
Wei (Mike) He, Senior technician

 


Selected Publications:

  • Haotian Zhang, Henry Tannous, Christopher Mazzeo, Haoyi Zheng, Huichun Zhan. Somatic mutations in both blood cells and vascular endothelium from patients with severe coronary artery diseases. (under review)
  • Lee S, Wong H, Castiglione M, Murphy M, Kaushansky K, Zhan H. JAK2V617F mutant megakaryocytes contribute to hematopoietic aging in a murine model of myeloproliferative neoplasm. Stem Cells, 2022.
  • Zhang H, Castiglione M, Zheng L, Zhan H. Cell competition between wild-type and JAK2V617F mutant cells prevents disease relapse after stem cell transplantation in a murine model of myeloproliferative ne oplasm. Experimental Hematology & Oncology. 2021
  • Zhang H, Yeware A, Lee S, Zhan H. A murine model with JAK2V617F expression in both hematopoietic cells and vascular endothelial cells recapitulates the key features of human myeloproliferative neoplasm. Frontiers in Oncology. 2021
  • Castiglione M, Zhang H, Kaushansky K, Zhan H. Cell competition between wild-type and JAK2V617F mutant cells in a murine model of a myeloproliferative neoplasm. Experimental Hematology. 2021. 
  • Mazzeo C, Quan M, Wong H, Castiglione M, Kaushansky K, Zhan H. JAK2V617F mutant endothelial cells promote neoplastic hematopoiesis in a mixed vascular microenvironment. Blood Cells, Molecules and Diseases. 2021. 
  • Melissa Castiglione,Ya-Ping Jiang, Christopher Mazzeo, Juei-Suei Chen, Kenneth Kaushansky, Wei Yin, Richard Z. Lin, Haoyi Zheng, Huichun Zhan. Endothelial JAK2V617F mutation leads to thrombosis, vasculopathy, and cardiomyopathy in a murine model of myeloproliferative neoplasm. Journal of Thrombosis and Haemostasis.  2020 Sep 13. doi: 10.1111/jth.15095.
  • Yu Zhang, Chi Hua Sarah Lin, Kenneth Kaushansky, Huichun Zhan. JAK2V617F Megakaryocytes Promote Hematopoietic Stem Cell Expansion in Mice through Thrombopoietin/MPL signaling.Stem Cells 2018 
  • Chi Hua Sarah Lin, Yu Zhang, Kenneth Kaushansky, Huichun Zhan. JAK2V617F-bearing Vascular Niche Enhances Malignant Hematopoietic Regeneration Following Radiation Injury. 2018 Haematologica doi: 10.3324 /haematol.2017.185736
  • Huichun Zhan, Chi Hua Sarah Lin, Yarden Segal, Kenneth Kaushansky. The JAK2V617F-bearing Vascular Niche Promotes Clonal Expansion in Myeloproliferative Neoplasms. Leukemia.2017 doi: 10.1038/leu.2017.233.
  • Chi Hua Sarah Lin, Kenneth Kaushansky, Huichun Zhan. JAK2V617F-mutant Vascular Niche Contributes to JAK2V617F Clonal Expansion in Myeloproliferative Neoplasms. Blood Cells, Molecules, and Diseases 2016 Nov; 62:42-48. doi: 10.1016/j.bcmd.2016.09.004.
  • Huichun Zhan, Yupo Ma, Chi Hua Sarah Lin, Kenneth Kaushansky. JAK2V617F-mutant Megakaryocytes Contribute to Stem Cell Expansion in Myeloproliferative Syndromes. Leukemia 2016 May 2. doi: 10.1038/leu.2016.114.
  • Huichun Zhan, Kristen Ciano, Katherine Dong, Stanley Zucker. Targeting Glutamine Metabolism in Myeloproliferative Neoplasms. Blood Cells, Molecules, and Diseases 2015 Oct; 55(3): 241-7.
  • Huichun Zhan, Christopher Cardozo, Azra Raza. MciroRNAs in Myeloproliferative Neoplasms. British Journal of Haematology 2013 161(4): 471-83.
  • Huichun Zhan, Christopher Cardozo, Wayne Yu, Antai Wang, Alison Moliterno, Chi Dang, Jerry Spivak. MicroRNA Deregulation in Polycythemia Vera and Essential Thrombocythemia Patients. Blood Cells, Molecules, and Diseases 2013 Mar; 50(3): 190-5.
  • Zhaohui Ye*, Huichun Zhan*, Prashant Mali, Sarah Dowey, Yoon-Young Jang, Chi V. Dang, Jerry L. Spivak, Alison R. Moliterno, and Linzhao Cheng. Derivation of human iPS cells from blood cells of patients with acquired blood disorders. Blood 2009 Dec; 114(27):5473-5480.
  • Huichun Zhan, Jerry Spivak. The Diagnosis and Management of Polycythemia Vera, Essential Thrombocytosis and Primary Myelofibrosis in the JAK2 V617F Era. Clinical Advances in Hematology and Oncology. 2009 May; 7(5): 334-42.
  • Huichun Zhan, Michael Streiff, Karen King, Jodi Segal. Thrombotic Thrombocytopenic Purpura at Johns Hopkins from 1992 to 2008: Clinical Outcomes and Risk Factors for Relapse. Transfusion. 2009.
  • Huichun Zhan, Lorraine J. Gudas, Dean Bok, Robert Rando, David M. Nanus, and Satish K. Tickoo. Differential Expression of the Enzyme Lecithin: Retinol Acyl Transferase in Subtypes of Human Renal Cancer and Normal Kidney. Clinical Cancer Research Oct.15 2003; 9 (13).
  • Huichun Zhan, Depei Liu. Insulator: From Chromatin Domain Boundary to Gene Regulation. Human Genetics Nov. 2001; 109(5): 471-8.