Two observations suggest that the Interferon Consensus Sequence Binding Protein (ICSBP) is necessary for normal myeloid differentiation. The first observation is that ICSBP -/- mice have myeloid expansion and impaired immune function. This suggests that ICSBP is necessary for progression of differentiation. The second observation is that ICSBP expression is decreased in human myeloid malignancy, and 1CSBP -/- mice develop myeloid leukemia. This suggests that ICSBP is a """"""""leukemia suppressor"""""""", during myeloid differentiation. We found that tyrosine phosphorylated ICSBP interacts with PU.1, Interferon Regulatory Factor 1, and the CREB-binding protein, during late myeloid differentiation. This interaction activates genes encoding the respiratory burst oxidase proteins, gp91phox and p67phoX. These results suggest that ICSBP activates transcription of genes that confer the mature phagocyte phenotype. In contrast, non-tyrosine phosphorylated ICSBP represses Bcl-XL expression in undifferentiated myeloid cells. This suggests that ICSBP influences initiation of apoptosis during early differentiation. Therefore, ICSBP tyrosine phosphorylation, which occurs during myelopoiesis, alters protein-DNA and protein-protein interactions. Based on these observations, we hypothesize that ICSBP participates in phosphorylation dependent protein-protein interactions, which regulate differentiation-stage-specific myeloid gene expression and are necessary for differentiation progression. We also hypothesize that ICSBP tyrosine phosphorylation induces functional switch from repressor to activator. The following aims will pursue these hypotheses;
Aim 1 : Determine if ICSBP tyrosine phosphorylation is necessary for progression of myeloid differentiation.
Aim 2 : Determine if ICSBP function switches from repression to activation during myeloid differentiation.
Aim 3 : Determine if ICSBP tyrosine phosphorylation is necessary for """"""""tumor suppression"""""""" in ICSBP -/- mice. These studies will determine if ICSBP tyrosine phosphorylation is necessary for myeloid differentiation and leukemia suppression, providing a unique model to dissect early events in the evolution of myeloid malignancy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CAMP (01))
Program Officer
Mufson, R Allan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Konieczna, Iwona; Horvath, Elizabeth; Wang, Hao et al. (2008) Constitutive activation of SHP2 in mice cooperates with ICSBP deficiency to accelerate progression to acute myeloid leukemia. J Clin Invest 118:853-67
Zhu, Chunliu; Lindsey, Stephan; Konieczna, Iwonna et al. (2008) Constitutive activation of SHP2 protein tyrosine phosphatase inhibits ICSBP-induced transcription of the gene encoding gp91PHOX during myeloid differentiation. J Leukoc Biol 83:680-91
Kakar, Renu; Kautz, Bryan; Eklund, Elizabeth A (2005) JAK2 is necessary and sufficient for interferon-gamma-induced transcription of the gene encoding gp91PHOX. J Leukoc Biol 77:120-7
Zhu, Chunliu; Saberwal, Gurveen; Lu, Yufeng et al. (2004) The interferon consensus sequence-binding protein activates transcription of the gene encoding neurofibromin 1. J Biol Chem 279:50874-85
Lu, YuFeng; Goldenberg, Inna; Bei, Ling et al. (2003) HoxA10 represses gene transcription in undifferentiated myeloid cells by interaction with histone deacetylase 2. J Biol Chem 278:47792-802
Eklund, Elizabeth A; Goldenberg, Inna; Lu, YuFeng et al. (2002) SHP1 protein-tyrosine phosphatase regulates HoxA10 DNA binding and transcriptional repression activity in undifferentiated myeloid cells. J Biol Chem 277:36878-88