Molecular Mechanisms of Disease Progression in Myeloid Malignancy

Summary

Principal Investigator: ELIZABETH ANN EKLUND
Abstract: DESCRIPTION (provided by applicant): The Interferon Consensus Sequence Binding Protein (Icsbp) is an interferon regulatory transcription factor that functions as a tumor-suppressor (also referred to as Irf8). During this Merit Review project, we used high throughput screening approaches to identify Icsbp-target-genes that mediate tumor-suppressor activity. We identified an Icsbp-target-gene set that is enriched for genes which control Fas-induced apoptosis and/or bcatenin activity. This is of interest, because decreased Icsbp-expression, Fas-resistance, and increased bcatenin activity are associated with poor prognosis in chronic myeloid leukemia (CML). Insensitivity of cancer/leukemia stem cells (CSC/LSC) to Fas-induced apoptosis is associated with development of drug resistance in CML, but does not correlate with decreased Fas/FasL. Increased [unreadable]catenin activity in CML- CSC/LSC precedes progression to blast crisis (BC), but does not correlate with Wnt expression or CTNNB1 transcription. Tyrosine kinase inhibitors (TKI) that target Bcr-abl (the CML oncogene) induce remission in the majority of patients. However, the CSC/LSC population expands during remission, preventing cure with TKIs. CSC/LSC persistence is hypothesized to be due to dysregulation of Fas and/or bcatenin. During the previous funding period, we identified Icsbp-target-genes that explain Fas-resistance and increased bcatenin activity in CML. We found that Icsbp represses PTPN13;the gene encoding Fap1. Fap1 interacts with and inhibits Fas, and we found Icsbp/Fap1-dependent Fas-resistance in cells expressing Bcr-abl. Fap1 also interacts with Apc, and we found inhibition of Gsk3b and stabilization of bcatenin in these cells. We identified GAS2 as another relevant Icsbp-target-gene. Gas2 inhibits calpain;a serine protease with substrates that include bcate-nin, Stat3, Stat5 and Xiap. We found a Gas2-dependent decrease in calpain activity and increase in bcatenin in Bcr-abl+ or Icsbp-/- murine bone marrow cells. Stat3, Stat5 and Xiap proteins are also increased in Icsbp-/- cells in a Gas2/calpain-dependent manner. Interestingly, we found that Stat5 represses the IRF8 promoter in a Gas2/calpain-dependent manner. Xiap inhibits caspase 3, contributing to Fas-resistance. We identified RASSF5, the gene encoding Nore1, as another Icsbp-target-gene. Nore1 activates Mst1;a kinase that facilitates caspase cleavage and therefore Fas-induced apoptosis. The hypothesis of these studies is that decreased expression of the tumor-suppressor Icsbp results in Fas-resistance and increased bcatenin activity. We also hypothesize that Icsbp-target-genes or cognate pathways would be rational therapeutic targets to prevent overt drug resistance and progression to BC in CML. This hypotheses will be pursued through three Aims;AIM 1: Define the role of Icsbp-dependent expression of Nore1 and Xiap in CML-LSC expansion. The contribution of Nore1a or Xiap to Fas-resistance and cooperation with Fap1 will be studied in CML-LSC. The impact of targeting these pathways on LSC expansion in an in vivo CML murine model will be determined. AIM 2: Determine if Icsbp contributes to disease progression by inhibiting Gsk3[unreadable] or increasing Stat3 in CML-LSC. Contribution of Gsk3[unreadable] and Stat3 to bcatenin activity will be studied in vitro and in vivo, as above. The effect of targeting these pathways on disease progression will be studied in an in vivo CML murine model. AIM 3: Identify the roles of Stat5 and Aml1 in IRF8 transcription and leukemogenesis. IRF8 transcriptional regulation by Bcr-abl-dependent Stat5 activation will be studied in studies with myeloid leukemia cell lines and with primary murine bone marrow cells. The role of targeting calpain to decrease Stat5 protein stability, and thereby increase Icsbp expression, will be investigated in murine models in vitro and in vivo. The goal of these studies is to identify molecular mechanisms for Icsbp tumor suppressor activity. Targeting these mechanisms may lead to cure in CML by abolishing the CSC/LSC, and suggest therapeutic approaches to other forms of cancer with dysregulation of Fas and bcatenin.
Funding Period: 2013-04-01 - 2017-03-31
more information: NIH RePORT

Research Grants

  1. The role of ICSBP in the pathogenesis of chronic myeloid leukemia
    ELIZABETH ANN EKLUND; Fiscal Year: 2013
  2. The Role of CREB in Normal Myelopoiesis and Leukemogenesis
    KATHLEEN MIHO SAKAMOTO; Fiscal Year: 2013
  3. P53 - REGULATORS AND EFFECTORS
    Stuart A Aaronson; Fiscal Year: 2013
  4. NK Cells, Their Receptors and Unrelated Donor Transplant
    Jeffrey S Miller; Fiscal Year: 2013
  5. M D Anderson Cancer Center Prosate SPORE
    Christopher J Logothetis; Fiscal Year: 2013
  6. Experimental Therapeutics of Leukemia
    John C Byrd; Fiscal Year: 2013
  7. Role of Vav and Rac in KIT oncogenesis
    Reuben Kapur; Fiscal Year: 2013
  8. Targeting PML for leukemia therapy.
    Pier Paolo Pandolfi; Fiscal Year: 2013
  9. Leukemia Stem Cells: Essential Targets for GVL and Mediators of GVL-Resistance
    Warren D Shlomchik; Fiscal Year: 2013
  10. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013

Detail Information

Research Grants30

  1. The role of ICSBP in the pathogenesis of chronic myeloid leukemia
    ELIZABETH ANN EKLUND; Fiscal Year: 2013
    ..The goal of these studies is to identify molecular mechanisms that lead to LSC persistence, and therefore TKI resistance and/or BC in CML. Targeting these mechanisms might cure CML by abolishing the LSC. ..
  2. The Role of CREB in Normal Myelopoiesis and Leukemogenesis
    KATHLEEN MIHO SAKAMOTO; Fiscal Year: 2013
    ..These studies will provide new insights into how CREB regulates normal hematopoiesis and contributes to leukemogenesis. ..
  3. P53 - REGULATORS AND EFFECTORS
    Stuart A Aaronson; Fiscal Year: 2013
    ..This Program brings together a senior group of investigators from different disciplines and with complementary expertise focused on important and novel aspects of p53 biology. ..
  4. NK Cells, Their Receptors and Unrelated Donor Transplant
    Jeffrey S Miller; Fiscal Year: 2013
    ..The program also promises to change practice of allogeneic transplantation, to the greater benefit of patients with advanced leukemia. ..
  5. M D Anderson Cancer Center Prosate SPORE
    Christopher J Logothetis; Fiscal Year: 2013
    ..We are optimistic that our research efforts will contribute to reductions in the incidence of, and morbidity and mortality from, this devastating disease by translating basic research into clinical practice. ..
  6. 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. ..
  7. Role of Vav and Rac in KIT oncogenesis
    Reuben Kapur; Fiscal Year: 2013
    ..abstract_text> ..
  8. Targeting PML for leukemia therapy.
    Pier Paolo Pandolfi; Fiscal Year: 2013
    ..The elucidation of the mechanisms by which PML regulates the maintenance of the LIC pool could in turn lead to novel therapeutic approaches to treat leukemia. ..
  9. Leukemia Stem Cells: Essential Targets for GVL and Mediators of GVL-Resistance
    Warren D Shlomchik; Fiscal Year: 2013
    ..Unfortunately, for reasons that are unknown, many cancers are resistant to this therapy and this proposal will investigate the biology underlying this differential sensitivity. ..
  10. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  11. 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. ..
  12. PAPOVA VIRUS TRANSFORMING MECHANISMS
    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. ..
  13. Analysis of the leukemic stem cell niche in chronic myeloid leukemia
    DANIELA SANDRA KRAUSE; Fiscal Year: 2013
    ..abstract_text> ..
  14. 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. ..
  15. MOLECULAR BASIS OF VIRAL AND CELLULAR TRANSFORMATION
    DANIEL C DIMAIO; Fiscal Year: 2013
    ..abstract_text> ..
  16. Targeting BCL6 in tyrosine kinase-driven leukemia
    MARKUS MUSCHEN; Fiscal Year: 2013
    ....
  17. H3K79 Methylation in Hematopoietic Stem Cell Development and MLL-Rearranged Leuk
    Kathrin M Bernt; Fiscal Year: 2013
    ..Stuart Schreiber. Execution of these aims will elucidate fundamental mechanisms of chromatin regulation in benign and malignant hematopoiesis. ..