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 11

AML from mice transplanted with E76K SHP2–expressing ICSBP+/– bone marrow was transplantable.

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AML from mice transplanted with E76K SHP2–expressing ICSBP+/– bone marro...
Irradiated WT mice were transplanted with cells isolated from mice that had been transplanted with control or E76K SHP2 expression vector–transduced ICSBP+/– bone marrow. Mice were followed with peripheral blood counts every 2 weeks. (A) Secondary recipient from mice that had been transplanted with E76K SHP2–expressing ICSBP+/– bone marrow rapidly developed AML. Peripheral blood counts of mice that had been transplanted with control or E76K SHP2 expression vector–transduced ICSBP+/– bone marrow were determined at 32 weeks and those of secondary recipients at 4 weeks after transplantation. The percentage of peripheral myeloid blasts was not significantly different in primary and secondary recipients with E76K SHP2–expressing ICSBP+/– cells. (B) MPD and AML developed in secondary recipients of E76K SHP2–expressing ICSBP+/– hematopoietic cells, but only MPD developed in secondary recipients with control ICSBP+/– cells. Peripheral blood counts were determined at 2 and 4 weeks. Mice transplanted with control ICSBP+/– cells developed a mild MPD. In contrast, E76K SHP2 expression resulted in more profound MPD and AML by 2 weeks. Significant differences in wbc are indicated by * and ** and in blasts by # and ## (P ≤ 0.001 for all comparisons). (C) Myeloid blasts in transplanted mice. Myeloid blasts from primary and secondary recipients of E76K SHP2–expressing ICSBP+/– hematopoietic cells are morphologically similar. Original magnification, ×40.