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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 9

E76K SHP2 cooperated with ICSBP haploinsufficiency for AML.

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E76K SHP2 cooperated with ICSBP haploinsufficiency for AML.
Development ...
Development of leukemia in mice transplanted with WT or ICSBP+/– bone marrow that was transduced with vectors to express WT or E76K SHP2 or vector control was monitored as described above. Mice with greater than 20% myeloid blasts were considered to have AML. The percent of mice without leukemia was plotted as a function of age. (A) Mice transplanted with ICSBP+/– bone marrow that was transduced with a vector to express E76K SHP2 rapidly developed AML. Fifty percent of these mice developed AML between 12 and 16 weeks after transplantation. In contrast, only 2 mice transplanted with either control or WT SHP2–overexpressing ICSBP+/– bone marrow developed AML during the observation period. (B) AML did not develop in mice transplanted with WT bone marrow that was transduced with E76K SHP2 expression vector. Few of these mice developed AML by 24 weeks. None of the mice transplanted with WT bone marrow transduced with control or SHP2 expression vector developed AML during the observation period.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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