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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 8

E76K SHP2 cooperated with ICSBP haploinsufficiency to accelerate AML.

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E76K SHP2 cooperated with ICSBP haploinsufficiency to accelerate AML.
WT...
WT irradiated mice were transplanted with WT or ICSBP+/– bone marrow that was transduced with a retroviral vector to express SHP2, E76K SHP2, or control. Peripheral blood counts were determined every 4 weeks for 24 weeks. (A) Mild MPD developed in mice transplanted with control ICSBP+/– bone marrow. These mice developed mild neutrophilia, but rare myeloid blasts. (B) Mild MPD developed in mice transplanted with WT SHP2-overexpressing ICSBP+/– bone marrow. These mice developed leukocytosis that was not significantly different from that in mice transplanted with control ICSBP+/– bone marrow. (C) MPD and rapid AML developed in mice transplanted with E76K SHP2–expressing-ICSBP+/– bone marrow. These mice developed leukocytosis that was significantly greater than that in mice transplanted with control or WT SHP2–overexpressing ICSBP+/– bone marrow (*P < 0.001) with significantly more myeloid blasts (**P < 0.01). (D) Peripheral blood counts were normal in mice transplanted with control vector–transduced WT bone marrow. These mice exhibited normal peripheral blood counts and leukocyte differential. (E) Peripheral blood counts were normal in mice transplanted with SHP2 expression vector–transduced WT bone marrow. These mice also exhibited normal peripheral blood counts and leukocyte differential. (F) Mild MPD developed in mice transplanted with E76K SHP2–expressing WT bone marrow. These mice exhibited significantly greater total leukocyte counts (*P < 0.001) than mice transplanted with control WT bone marrow with significant neutrophilia (**P < 0.001). (G) Mice transplanted with E76K SHP2–expressing ICSBP+/– bone marrow developed splenomegaly. Spleens harvested from these mice were significantly larger than those from mice transplanted with control or WT SHP2–overexpressing ICSBP+/– bone marrow.

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