RIZ1 repression is associated with insulin-like growth factor-1 signaling activation in chronic myeloid leukemia cell lines

Abstract

RIZ1 is a histone methyltransferase whose expression and activity are reduced in many cancers. In chronic myelogenous leukemia (CML), blastic transformation is associated with loss of heterozygosity in the region where RIZ1 is located and with decreased RIZ1 expression. Forced RIZ1 expression in model CML blast crisis (BC) cell lines decreases proliferation, increases apoptosis and enhances differentiation. We characterized molecular mechanisms that may contribute to potential CML tumor suppressor properties of RIZ1. Several RIZ1-regulated genes involved in insulin-like growth factor-1 (IGF-1) signaling were identified using cDNA microarrays. RIZ1 was shown to associate with promoter regions of IGF-1 and to increase histone H3 lysine 9 methylation using chromatin immunoprecipitation assays. IGF-1-blocking antibody was used to demonstrate the importance of autocrine IGF-1 signaling in CML-BC cell line viability. Forced RIZ1 expression in CML-BC cell lines decreases IGF-1 receptor activation and activation of downstream signaling components extracellular signal-regulated kinase 1/2 and AKT. These results highlight the therapeutic potential of inhibiting IGF-1 pathway in the acute phase of CML.

Epigenetic regulation of normal and malignant hematopoiesis

“…Many cancer-associated mutations in RIZ affect its HMT activity, suggesting an important role for this activity in suppression of tumor formation (Kim et al, 2003). RIZ1 knockout mice develop B-cell lymphoma (Steele-Perkins et al, 2001), and in chronic myelogenous leukemia (CML), blastic transformation is associated with loss of heterozygosity in the vicinity of RIZ1 and a decrease in RIZ1 expression (Pastural et al, 2007). Overexpression of RIZ1 in a model CML blast crisis cell line also reduced cellular proliferation and enhanced differentiation, confirming a potential tumor suppressor role mediated by RIZ1.…”

Bcr-Abl induces autocrine IGF-1 signaling

“…Previously, we showed that an IGF-1R blocking antibody reduces the viability of CML BC cell lines (Pastural et al, 2007). Similarly, AG1024 has been shown to inhibit clonogenic survival, proliferation and xenograft tumor growth, while enhancing apoptosis (Deutsch et al, 2004).…”

“…Previously, we showed that Riz1 represses IGF-1 expression in CML BC cell lines (Pastural et al, 2007). To examine whether IGF-1 expression is enhanced in CML BC, we performed immunohistochemistry using an anti-IGF-1 antibody to measure IGF-1 expression in matched patient biopsies from CP and BC (Figure 1).…”

“…We recently investigated the role of the putative tumor suppressor Riz1 in CML (Pastural et al, 2007), which is located at chromosome region 1p36 and undergoes loss of heterozygosity during the transformation from CP to BC (Mori et al, 1998). Riz1 expression is reduced in BC (Takahashi et al, 2006) and in CML BC cell lines Riz1 represses insulin-like growth factor 1 (IGF-1) expression and autocrine signaling (Pastural et al, 2007).…”

“…IGF-1 is also important in leukemogenesis as seen by its ability to stimulate myeloid and lymphoid cells in culture (Johnson et al, 1992;Schwartz et al, 1996), to stimulate proliferation of CML BC cell lines (Hizuka et al, 1987), to increase bone marrow blast colony formation in patients with acute myeloid leukemia (AML; Zadik et al, 1993) and to promote growth of AML blasts (Doepfner et al, 2007). IGF-1 mediated effects can be inhibited by IGF-1 receptor (IGF-1R) blocking antibodies (Merchav et al, 1988a;Doepfner et al, 2007;Pastural et al, 2007) and inhibitors AG1024 (Deutsch et al, 2004) and NVP-AEW541 (Doepfner et al, 2007;Tazzari et al, 2007).…”