ICSBP Function During Myeloid Differentiation

Summary

Principal Investigator: Elizabeth Eklund
Affiliation: Northwestern University
Country: USA
Abstract: DESCRIPTION (provided by applicant): Several lines of evidence suggest that the interferon consensus sequence binding protein (ICSBP or IRF8) functions as a myeloid leukemia tumor-suppressor. First, ICSBP-expression is decreased in bone marrow samples from subjects with myelodysplastic syndrome (MDS) and chronic myeloid leukemia (CML). Second, mice with targeted disruption of the IRF8-gene exhibit a CML-like myeloproliferative disorder which progresses to acute myeloid leukemia (AML) over time. These results suggest that ICSBP-deficiency alone is adequate to induce myeloproliferation, but additional mutations are necessary for progression to AML. However, initially identified target-genes did not suggest a mechanism by which ICSBP-deficiency predisposes to either of these events. For example, we found that ICSBP activates transcription of genes encoding the phagocyte NADPH-oxidase proteins, gp91PHOX and p67phox. Other investigators identified additional ICSBP-target-genes involved in phagocyte function. Therefore, ICSBP-deficiency decreases myeloid-specific gene transcription, which may contribute to differentiation block. However, ICSBP-deficient myeloid progenitor cells exhibit resistance to apoptosis, hypersensitivity to hematopoietic cytokines, and the tendency to accumulate additional genetic lesions. Genuine ICSBP-target-genes mediating these effects had not been identified. During the previous funding period, we pursued identification of such target-genes. Using chromatin immuno-precipitation and CpG island microarray screening, we identified ICSBP- target-genes which encode proteins involved in proliferation (Neurofibromin 1) and apoptosis (Nore1, Fap1 and a soluble guanylate cyclase component). Identification of these target-genes supports the hypothesis that ICSBP-deficiency is sufficient to induce a myeloproliferative disorder. We also identified target-genes involved in hematopoietic stem cell expansion via regulation of the Wnt/2catenin pathway (Gas2, Dapper2 and calpain2 and 12). Additionally, we identified an ICSBP-target-gene involved in a key DNA repair pathway in hematopoietic cells (Fanconi F). This is consistent with the hypothesis that abnormal target-gene expression ICSBP-deficient cells predisposes to acquisition of additional genetic mutations, leading to differentiation block and AML. We will pursue our hypotheses through the following specific aims;Aim 1: Determine if abnormal expression of apoptosis-related target-genes contributes to myeloproliferation in ICSBP-deficient hematopoiesis. Aim 2: Determine if abnormal expression of target-genes which regulate DNA-repair and hematopoietic stem cell expansion predisposes to AML in ICSBP-deficient hematopoiesis. Aim 3: Identify genetic lesions that cooperate with ICSBP-deficiency to lead to disease progression in myeloid malignancy. PUBLIC HEALTH RELEVANCE: Identifying ICSBP-target-genes may suggest common final pathways which is sufficient for myeloproliferation and necessary for susceptibility to myeloid blast crisis. Functional characterization of such a pathway has implications for identifying early markers of disease progression in human myeloid malignancy and rational targets for molecular therapeutic approaches to diseases such as CML and MDS.
Funding Period: ----------------2008 - ---------------2012-
more information: NIH RePORT

Top Publications

  1. doi Fas-associated phosphatase 1 mediates Fas resistance in myeloid progenitor cells expressing the Bcr-abl oncogene
    Weiqi Huang
    The Feinberg School of Medicine and the Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
    Leuk Lymphoma 54:619-30. 2013
  2. pmc Increased Fanconi C expression contributes to the emergency granulopoiesis response
    Liping Hu
    Feinberg School of Medicine and Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA
    J Clin Invest 123:3952-66. 2013
  3. pmc The interferon consensus sequence binding protein (ICSBP/IRF8) activates transcription of the FANCF gene during myeloid differentiation
    Gurveen Saberwal
    The Feinberg School of Medicine and Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611, USA
    J Biol Chem 284:33242-54. 2009
  4. pmc Genomic analysis of acute myeloid leukemia: potential for new prognostic indicators
    Elizabeth A Eklund
    The Feinberg School of Medicine, Northwestern University, Jesse Brown VA Medical Center, Chicago, Illinois, USA
    Curr Opin Hematol 17:75-8. 2010
  5. pmc Interferon consensus sequence binding protein (ICSBP) decreases beta-catenin activity in myeloid cells by repressing GAS2 transcription
    Weiqi Huang
    Feinberg School of Medicine and Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA
    Mol Cell Biol 30:4575-94. 2010

Scientific Experts

  • Elizabeth Eklund
  • Weiqi Huang
  • Liping Hu
  • Gurveen Saberwal
  • Elizabeth Hjort
  • Elizabeth Horvath
  • Ling Bei
  • Leonidas C Platanias
  • Wei Zhou
  • Iwona Konieczna
  • Efstratios Katsoulidis
  • Chunliu Zhu

Detail Information

Publications5

  1. doi Fas-associated phosphatase 1 mediates Fas resistance in myeloid progenitor cells expressing the Bcr-abl oncogene
    Weiqi Huang
    The Feinberg School of Medicine and the Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
    Leuk Lymphoma 54:619-30. 2013
    ..Therefore, these results have implications for therapeutic targeting of the Fas-resistant leukemia stem cell population and addressing TKI resistance in CML...
  2. pmc Increased Fanconi C expression contributes to the emergency granulopoiesis response
    Liping Hu
    Feinberg School of Medicine and Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA
    J Clin Invest 123:3952-66. 2013
    ..These studies have implications for understanding the pathogenesis of bone marrow failure in Fanconi anemia and suggest possible therapeutic approaches...
  3. pmc The interferon consensus sequence binding protein (ICSBP/IRF8) activates transcription of the FANCF gene during myeloid differentiation
    Gurveen Saberwal
    The Feinberg School of Medicine and Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611, USA
    J Biol Chem 284:33242-54. 2009
    ..Our studies suggest that ICSBP deficiency may be functionally important for accumulation of chromosomal abnormalities during disease progression in these myeloid malignancies...
  4. pmc Genomic analysis of acute myeloid leukemia: potential for new prognostic indicators
    Elizabeth A Eklund
    The Feinberg School of Medicine, Northwestern University, Jesse Brown VA Medical Center, Chicago, Illinois, USA
    Curr Opin Hematol 17:75-8. 2010
    ..These findings advanced the ability to predict outcome and to tailor treatments in AML. These studies also suggested that a more detailed analysis of somatic genomic mutations might extend these advances...
  5. pmc Interferon consensus sequence binding protein (ICSBP) decreases beta-catenin activity in myeloid cells by repressing GAS2 transcription
    Weiqi Huang
    Feinberg School of Medicine and Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA
    Mol Cell Biol 30:4575-94. 2010
    ..Therefore, these studies have identified a Gas2/calpain-dependent mechanism by which ICSBP influences beta-catenin activity in myeloid leukemia...