ICSBP Haplo-Insufficiency Synergizes with SHP2-Activation for Apoptosis Resistance and Cytokine Hypersensitivity in Myeloid Progenitors.

Abstract

The interferon consensus sequence binding protein (ICSBP or IRF8) is an interferon regulatory transcription factor which functions as a myeloid leukemia tumor-suppressor. In mice, ICSBP-deficiency was found to induce a myeloproliferative disorder (MPD) which progressed to acute myeloid leukemia (AML) over time. This result suggested that ICSBP-deficiency was sufficient for myeloproliferation, but additional genetic lesions were required for differentiation block and therefore AML. ICSBP-deficiency has been described in human myeloid malignancies including myelodysplastic syndrome (MDS), AML and uncontrolled chronic myeloid leukemia (CML). Other previous studies determined that cytokine-induced ICSBP-tyrosine-phosphorylation was required for differentiation-stage-specific target-gene transcription during myelopoiesis. Based on these results, we hypothesized that impaired ICSBP-tyrosine-phosphorylation might exacerbate the impact of ICSBP-deficiency and induce differentiation block and progression from MPD to AML. However, leukemia-associated mutations which impaired tyrosine-phosphorylation had not been described in the gene encoding ICSBP. Therefore, we hypothesized that mutations influencing the molecular pathways involved in ICSBP-post-translational-modification might synergize with ICSBP-deficiency to accelerate progression to AML. SHP2 protein tyrosine phosphatase was previously found to dephosphorylate ICSBP in immature myeloid cells. Additional studies determined that a leukemia-associated, constitutively-active form of SHP2 de-phosphorylated ICSBP through out myelopoiesis. In the current studies, we investigated the ability of constitutive SHP2-activation to synergize with ICSBP haplo-insufficiency to induce cytokine-hypersensitivity and apoptosis-resistance. We also investigated the impact of constitutive SHP2-activation on the tumor suppressor effect of ICSBP. Both ICSBP-deficiency and constitutively active mutants of SHP2 have been described in subjects with therapy related MDS/AML. Also, activity of the bcr/abl kinase induces both SHP2 activation and ICSBP-deficiency. Therefore, our studies identified a molecular mechanism which might be involved in disease progression in these human myeloid diseases.