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 10

Constitutive SHP2 activation synergized with ICSBP deficiency to induce HSC expansion and differentiation block.

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Constitutive SHP2 activation synergized with ICSBP deficiency to induce ...
Mice were analyzed after transplantation for bone marrow gene expression. (A) SHP2 was equivalently overexpressed in mice transplanted with WT or ICSBP+/– bone marrow that was transduced WT or E76K SHP2 expression vector. Expression of the SHP2 transgene was determined by real-time PCR using a primer set that detected both WT and E76K SHP2. There was no significant difference in the extent of overexpression of SHP2 or E76K SHP2 in WT (*P = 0.006) or ICSBP+/– (**P = 0.04) bone marrow at 24 weeks. (B) E76K SHP2 expression in ICSBP+/– bone marrow expanded the HSC and immature progenitor pool. CD34 expression in the bone marrow was determined by real-time PCR. Bone marrow CD34 expression was significantly greater in mice transplanted with control ICSBP+/– bone marrow in comparison to mice transplanted with control WT bone marrow (*P < 0.02). CD34 expression was not significantly different in mice transplanted with WT bone marrow that was transduced with any of these vectors. Bone marrow CD34 expression was significantly greater in mice transplanted with E76K SHP2–expressing ICSBP+/– bone marrow in comparison to ICSBP+/– controls (**P = 0.02). (C) E76K SHP2 expression in WT or ICSBP+/– bone marrow decreased gp91phox expression. gp91phox expression was determined by real-time PCR. Overexpression of WT SHP2 did not significantly decrease gp91phox expression in WT or ICSBP+/– bone marrow. E76K SHP2 expression significantly decreased gp91phox expression in comparison to control WT (*P = 0.003) or ICSBP+/– (**P = 0.008) bone marrow.