The inositol phosphatase SHIP-1 is negatively regulated by Fli-1 and its loss accelerates leukemogenesis

Abstract

The activation of Fli-1, an Ets transcription factor, is the critical genetic event in Friend murine leukemia virus (F-MuLV)-induced erythroleukemia. Fli-1 overexpression leads to erythropoietin-dependent erythroblast proliferation, enhanced survival, and inhibition of terminal differentiation, through activation of the Ras pathway. However, the mechanism by which Fli-1 activates this signal transduction pathway has yet to be identified. Down-regulation of the Src homology 2 (SH2) domain-containing inositol-5-phosphatase-1 (SHIP-1) is associated with erythropoietin-stimulated IntroductionThe progression of cancer is a multistep process in which oncogenes and tumor suppressor genes mediate changes in gene expression required for malignant transformation. Transcription factors, often described as oncogenes or tumor suppressor genes, play a pivotal role within signal transduction pathways governing cellular proliferation, differentiation, and apoptosis. 1 In Friend murine leukemia virus (F-MuLV)-induced erythroleukemia, the transcription factor fli-1 is activated as a result of proviral integration. A proto-oncogene and member of the Ets family of transcription factors, fli-1 plays a critical role in normal development, hematopoiesis and oncogenesis. [2][3][4][5][6] Accordingly, a recent study from our group, and that of another laboratory, has demonstrated that Fli-1 inhibition suppresses growth and induces cell death in murine and human erythroleukemias. 7,8 Fli-1 overexpression in erythroblasts blocks erythroid differentiation that is associated with activation of the Shc/Ras pathway in response to erythropoietin (Epo) stimulation. 9 The Src homology 2 (SH2) domain-containing inositol-5-phosphatase-1 (SHIP-1) is associated with phosphorylated Shc in Epo-stimulated erythroleukemic cells, 9 and correlates with increased proliferation of transformed erythroid cells. 10 Because SHIP-1 is involved in the regulation of extracellular signal-regulated kinase/mitogenactivated protein kinase (ERK/MAPK) and phosphatidylinositol 3-kinase (PI 3-K) signaling pathways, 11,12 we hypothesized that Fli-1 may promote Epo-induced proliferation, and activation of the above mentioned pathways, in part, through regulation of SHIP-1.SHIP-1 plays a role in the activation and proliferation of myeloid cells, macrophages, and mast cells. This phosphatase also negatively regulates c-Jun NH2-terminal kinase (JNK), 13 and nuclear factor-B (NF-B) activity. 14 SHIP-1 is expressed exclusively in hematopoietic cells and developing spermatogonia and is activated after cytokine, growth factor, or immunoreceptor activation in hematopoietic cells. 12,14,15 SHIP-1 is expressed in mature T cells, granulocytes, monocytes/macrophages, mast cells, and platelets. 16 Interestingly, it has been documented that SHIP-1 expression is turned off during erythropoiesis, specifically in TER119ϩ erythroid cells. 15 Expression of a short form of SHIP-1 (termed s-SHIP) modulates the activation threshold of primitive stem cells. 17,18 SHIP-1 knockout mice are viable b...

Therapeutic Potential of SH2 Domain-Containing Inositol-5′-Phosphatase 1 (SHIP1) and SHIP2 Inhibition in Cancer

“…Here we demonstrate that chemical inhibition of SHIP1 can eliminate residual disease in a lethal MM tumor model. Our results with chemical inhibition of SHIP suggest that SHIP has a tumor-promoting role in human myeloid leukemias and MM via its synthesis of PtdIns(3,4)P 2 , whereas other recent studies indicate SHIP can serve as a tumor suppressor in murine virally induced erythroid leukemia (35) and murine B cell lymphoma (36). In these latter models, it will be critical to determine whether inappropriate induction of s-SHIP or SHIP2 expression has occurred in these SHIP1 mutant tumor models and thus provided a compensatory enzymatic source of PtdIns(3,4)P 2 .…”

Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155

“…Although there has been no report of the role in human cancer (Gilby et al, 2007), ablation of SHIP-1 gene in mice leads to myeloproliferative disease (Helgason et al, 1998;Lakhanpal et al, 2010). SHIP-1 deficiency might explain other characteristics of MDS.…”

Abnormal expression of FLI1 protein is an adverse prognostic factor in acute myeloid leukemia

“…5,25-30 SHIP-1 is directly negatively regulated by FLI1, and the resulting loss of inositol phosphatase activity was associated with accelerated leukemogenesis. 31 The effects of altered FLI1 expression at the protein level have not been well studied.…”