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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088747-08
Application #
8123347
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Thomas, John
Project Start
2008-08-11
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
8
Fiscal Year
2011
Total Cost
$377,500
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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