Identification of novel target genes for polycythemia vera (PV)


Principal Investigator: Shaoguang Li
Abstract: DESCRIPTION (provided by applicant): The JAK2V617F mutation is found in the majority of myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia and primary myelofibrosis. Similar to chromosome- positive (Ph+) chronic myeloid leukemia (CML), these Philadelphia chromosome-negative (Ph-) MPNs are also derived from hematopoietic stem cells (HSCs) and have a risk of developing thrombosis and acute leukemia. There are still no curative therapies for these Ph- MPNs. Recent discovery of the JAK2V617F mutation has promoted the development of targeted therapy using JAK2 inhibitors to inhibit the function of JAK2V617F. Although some early-stage clinical trials show improvement of symptoms and quality of life in patients, the long-term effectiveness of these JAK2 inhibitors remains to be determined. There are already some concerns for the side effects of these drugs. On the other hand, it has been shown that inhibition of JAK2V617F with a JAK2 inhibitor does not eradicate PV-initiating cells, implying that inhibition of the kinase activity o JAK2V617F with a JAK2 inhibitor is unlikely to cure MPNs, which is a situation similar to the treatment of Ph+ CML with BCR-ABL kinase inhibitors that control but do not cure CML. The development of a curative therapy for MPNs requires in-depth studies of the molecular basis of JAK2V617F in initiation and maintenance of these diseases for identifying new and effective target genes. In this application, we focus on PV, a major form of MPNs associated with JAK2V617F. We have observed that Ph+ CML and Ph- MPNs involve the same HSC cell population and have similar myeloproliferative phenotype, suggesting that the disease-initiating cells for CML and PV might share some common regulatory mechanisms. My laboratory has a history of studying the biology and molecular targeting of CML-initiating cells or leukemia stem cells (LSCs) in CML, and we show that the survival and self-renewal of LSCs require the arachidonate 5- lipoxygenase gene (Alox5) and that Alox5 is essential for CML development (Chen et al. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nature Genetics 41:783-792, 2009). We also show that inhibition of Alox5 function leads to eradication of LSCs and prolonged survival of CML mice. Our preliminary data show that JAK2V617F activates Alox5 and loss of the Alox5 gene impedes the development of JAK2V617F-induced PV in mice, which is supported by prolonged survival of PV mice treated with an Alox5 inhibitor. These preliminary results allow us to hypothesize that Alox5 plays a significant role in the development of PV induced by JAK2V617F and is a potential target gene for the treatment of PV. The specific aims are: 1) To determine signaling pathways involved in Alox5 activation by JAK2V617F;and 2) To test whether inhibition of the Alox5 pathway suppresses mouse and human PV cells. These studies will build a solid foundation for future PV clinical trials by targeting the Alox5 pathway.
Funding Period: 2012-09-26 - 2014-06-30
more information: NIH RePORT

Detail Information

Research Grants30

  1. Role of NF-kB in hematopoietic stem cells and leukemia-initiating cell formation
    Christopher A Klug; Fiscal Year: 2013
    ..This proposal will examine the role of NF-?B in normal hematopoietic stem/progenitor cell function and test whether activation of NF-?B is sufficient to initiate and/or maintain LIC activity in AML. ..
  2. Mechanisms of Hematopoietic Stem Cell Maintenance
    Emmanuelle Passegue; Fiscal Year: 2013
    ..These experiments will uncover how corruption of a mechanism of cell preservation normally used by HSCs to maintain blood homeostasis contributes to the aberrant function of transformed HSCs and the development of myeloid malignancies. ..
  3. Functional and Molecular Dissection of Myeloproliferative Neoplasm Stem Cells
    Ann Mullally; Fiscal Year: 2013
    ..Finally, the candidate has recruited Dr. Ross Levine, one of the initial scientific investigators to describe the JAK2V617F mutation in MPN, as a collaborator for her project. ..
  4. Experimental Therapeutics of Leukemia
    John C Byrd; Fiscal Year: 2013
    ..We believe that this SPORE group, as a multidisciplinary, highly interactive and accomplished team, will have a substantial impact on improving the clinical outcome of leukemia patients. ..
  5. Epidemiology of Breast Cancer Subtypes in African American Women: a Consortium
    Julie R Palmer; Fiscal Year: 2013
    ..By pooling our data, specimens, and importantly, expertise to investigate these synergist hypotheses, we will elucidate much of the etiology of aggressive, early onset breast cancers in AA women. ..
  6. Host Defense Against HIV-related Pulmonary Infections
    Judd E Shellito; Fiscal Year: 2013
    ..abstract_text> ..
  7. The p110 alpha and delta isoforms of PI3 kinase in hematopoiesis and leukemia
    Kira Gritsman; Fiscal Year: 2013
    ..This proposal will use mouse knockout models to examine whether the p110 and p110 subunits of PI3 kinase are important for normal HSC function and are feasible targets for leukemia therapy. ..
    Ronald Hoffman; Fiscal Year: 2013
    ..abstract_text> ..
  9. Explosive Evolution Under Stress: The Driving Forces of Cancer Dynamics (Main)
    Robert H Austin; Fiscal Year: 2013
    ..Modern techniques of physical probes, genomics, proteomics and nanotechnology will allow us to analyze the evolutionary path of these emergent resistant cells. ..
  10. MicroRNA Deregulation in JAK2V617F-positive Chronic Myeloid Neoplasms
    Huichun Zhan; Fiscal Year: 2013
  11. Targeting BCL6 in tyrosine kinase-driven leukemia
    MARKUS MUSCHEN; Fiscal Year: 2013
  12. Role of JAK2V617F in the Pathogenesis of Myeloproliferative Disorders.
    Golam Mohi; Fiscal Year: 2013
    ..The results of these studies may identify new therapeutic targets for MPDs. Moreover, our inducible JAK2V617F knock-in mouse will provide a unique and reproducible animal model to test novel therapies for JAK2V617F-associated MPDs. ..
  13. Mechanisms of drug resistance in Myeloproliferative neoplasms treated with JAK2 i
    Mohammad Azam; Fiscal Year: 2013
  14. Studies of BCR-ABL leukemogenesis in mice
    Richard A Van Etten; Fiscal Year: 2013
    ..Together, these studies should yield important new knowledge that will improve the effectiveness of our current treatments for Ph+ leukemia, and increase the proportion of patients that are cured of their disease. ..
    STEPHEN TRACY OH; Fiscal Year: 2013
    ..Thus, the proposed studies and training environment will facilitate the candidate's long-term goal to become a successful independent investigator. ..
    DAVID MORSE LIVINGSTON; Fiscal Year: 2013
    ..The goal of this Program is to continue to shed new light on cellular transformation events that also underpin human cancer development and generate insights that lead to new cancer therapeutic strategies. ..
  17. Arterial Dysfunction: Basic and Clinical Mechanisms
    Thomas Michel; Fiscal Year: 2013
    ..Gladyshev. P. Libby directs the Redox Biomarkers Core;metabolic characterizations of mouse models studied in this Program will take place at the Yale Mouse Metabolic Phenotyping Center, led by G. Shulman. ..
  18. Molecular Pathways to Thynmic Lymphoma and Leukemia
    A Thomas Look; Fiscal Year: 2013
    ..Such interactions are expected to accelerate the pace at which important discoveries are generated in these projects and in the program as a whole. ..
  19. HSC Diversity: Regulation by Clonal Selection vs Epigenetic Induction
    Irving L Weissman; Fiscal Year: 2013
  20. Analysis of the leukemic stem cell niche in chronic myeloid leukemia
    DANIELA SANDRA KRAUSE; Fiscal Year: 2013
    ..abstract_text> ..
  21. Role of Setbp1 in leukemic stem cell self-renewal
    Yang Du; Fiscal Year: 2013
    ..Our study will also test whether targeting LSC self-renewal is efficient in treating CML blast crisis for which no effective treatments are currently available. ..
  22. Hyaluronan Matrices in Vascular Pathologies
    Vincent C Hascall; Fiscal Year: 2013
    ..abstract_text> ..
  23. The role of c-Maf in Stem cells in Leukemia
    UJUNWA CYNTHIA OKOYE; Fiscal Year: 2013