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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

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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 3

ICSBP tyrosine phosphorylation regulated apoptosis in differentiating myeloid cells.

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ICSBP tyrosine phosphorylation regulated apoptosis in differentiating my...
(A) Regulation of apoptosis by ICSBP is tyrosine phosphorylation dependent. Myeloid progenitors were isolated from the bone marrow of ICSBP–/– or WT mice and cultured in GM-CSF and IL-3. ICSBP–/– cells were transduced with a retroviral vector to express ICSBP, Y-mut ICSBP, or vector control. WT cells were transduced with vector control. Apoptosis was determined after 48 hours in a dose titration of IL-3 by annexin V staining. In comparison to WT cells, ICSBP–/– cells that had been transduced with empty vector or Y-mut ICSBP expression vector exhibited significantly less apoptosis at the lowest IL-3 doses (*P < 0.02). Apoptosis in ICSBP–/– cells transduced with a vector to express WT ICSBP was not significantly different from that in WT cells. (B) WT and Y-mut ICSBP are equivalently expressed in myeloid progenitors. Lysate proteins from the transduced ICSBP–/– cells, discussed above, were analyzed for ICSBP expression by Western blotting. Blots were serially probed with antibodies against ICSBP and actin (as a loading control).

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