Constitutive activation of SHP2 in mice cooperates with ICSBP deficiency to accelerate progression to acute myeloid leukemia
Iwona Konieczna, … , Leonidas Platanias, Elizabeth A. Eklund
Iwona Konieczna, … , Leonidas Platanias, Elizabeth A. Eklund
Published February 1, 2008
Citation Information: J Clin Invest. 2008;118(3):853-867. https://doi.org/10.1172/JCI33742.
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Research Article Hematology

Constitutive activation of SHP2 in mice cooperates with ICSBP deficiency to accelerate progression to acute myeloid leukemia

Abstract

Myeloproliferative disorders (MPDs) are characterized by cytokine hypersensitivity and apoptosis resistance. Development of a block in myeloid differentiation is associated with progression of MPD to acute myeloid leukemia (AML) and portends poor prognosis. Identifying molecular markers of this transition may suggest targets for therapeutic intervention. Interferon consensus sequence binding protein (ICSBP, also known as IRF8) is an interferon-regulatory transcription factor that functions as a leukemia tumor suppressor. In mice, ICSBP deficiency induces an MPD that progresses to AML over time, suggesting that ICSBP deficiency is sufficient for myeloproliferation, but additional genetic lesions are necessary for AML. Since activity of ICSBP is influenced by tyrosine phosphorylation state, we hypothesized that mutations in molecular pathways that regulate this process might synergize with ICSBP deficiency for progression to AML. Consistent with this, we found that constitutive activation of SHP2 protein tyrosine phosphatase synergized with ICSBP haploinsufficiency to facilitate cytokine-induced myeloproliferation, apoptosis resistance, and rapid progression to AML in a murine bone marrow transplantation model. Constitutive SHP2 activation cooperated with ICSBP deficiency to increase the number of progenitors in the bone marrow and myeloid blasts in circulation, indicating a block in differentiation. Since SHP2 activation and ICSBP deficiency may coexist in human myeloid malignancies, our studies have identified a molecular mechanism potentially involved in disease progression in such diseases.

Authors

Iwona Konieczna, Elizabeth Horvath, Hao Wang, Stephan Lindsey, Gurveen Saberwal, Ling Bei, Weiqi Huang, Leonidas Platanias, Elizabeth A. Eklund

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Figure 1

ICSBP tyrosine phosphorylation influenced target gene transcription.

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ICSBP tyrosine phosphorylation influenced target gene transcription. (A)...
(A) Representation of tyrosine residues in ICSBP. The ICSBP amino acid sequence contains 12 tyrosine residues, including 2 highly conserved residues in the IRF domain (indicated by *). (B) The switch from PRDI cis element repression to activation during myelopoiesis is mediated by non–IRF domain ICSBP tyrosines. U937 cells were transfected with an artificial promoter construct containing 4 copies of the PRDI consensus (PRDITATACAT) or control (TATACAT) and a vector to express ICSBP; ICSBP with mutation of conserved IRF domain tyrosines (Y92/95F ICSBP); or all 12 tyrosines (Y-mut ICSBP). Reporter assays were performed with or without IFN-γ. The PRDI cis element was equivalently repressed by all forms of ICSBP in undifferentiated transfectants (statistically significant results are indicated by *P ≤ 0.04). Differentiation increased PRDI cis element activity in transfectants with ICSBP, Y92/95F ICSBP, or vector control. This increase was not significantly different with WT versus Y92/95F ICSBP (**P ≤ 0.04). Repression activity of Y-mut ICSBP was not significantly altered by IFN-γ. (C) WT and Y-mut ICSBP were equivalently expressed in U937 transfectants. U937 cells were stably transfected with a vector to express ICSBP or Y-mut ICSBP, or vector control. Total lysate proteins were analyzed by Western blotting for ICSBP and tubulin (as a loading control). (D) WT and Y-mut ICSBP were similarly expressed in the nucleus. U937 cells were stably transfected with a vector to express epitope-tagged WT or Y-mut ICSBP, or vector control. Nuclear proteins from these transfectants were immunoprecipitated with an anti-ICSBP antibody and Western blotting performed with an anti–epitope tag antibody.