Bcr/Abl Increases Bcatenin Protein and Activity in An ICSBP-Dependent Manner in Myeloid Cells.

Abstract 2958

Poster Board II-934

The interferon consensus sequence binding protein (ICSBP) is an interferon regulatory transcription factor (also referred to as IRF8). Similar to other IRF proteins, ICSBP regulates transcription of genes involved in the inflammatory response. However, ICSBP also functions as a myeloid leukemia tumor suppressor. Specifically, decreased ICSBP expression in myeloid progenitor cells results in cytokine hypersensitivity and resistance to apoptosis in response to Fas-activation or IL3 withdrawal. Consistent with function as a tumor suppressor, decreased ICSBP-expression is found in the bone marrow of human subjects with chronic myeloid leukemia (CML). Expression of ICSBP increases during remission and decreasing ICSBP expression is associated with progression to CML blast crisis (BC). In murine models, ICSBP-deficiency induces a myeloproliferative disorder (MPD) which resembles CML. And, ICSBP overexpression blocks MPD in mice transplanted with Bcr/abl expressing bone marrow. Increased Bcatenin activity is also associated with CML-BC. However, the impact of ICSBP on Bcatenin expression or activity has not been previously investigated. In these studies, we hypothesized that ICSBP-deficiency in CML-BC increases Bcatenin-expression. In support of this hypothesis, we found that Bcatenin protein and activity were increased in myeloid cell lines with ICSBP-knock-down and decreased in cells with ICSBP-overexpression. Bcatenin protein and activity were also increased in primary myeloid progenitors from ICSBP-/- mice in comparison to wild type or ICSBP+/- mice, in an ICSBP-dose dependent manner. Expression of Bcr/abl decreased ICSBP-expression in myeloid cells and increased Bcatenin protein and activity. Also supporting our hypothesis, the effect of Bcr/abl on Bcatenin was abolished by re-expression of ICSBP in Bcr/abl expressing myeloid cell lines or primary murine myeloid progenitor cells. In each of these situations, the increase in Bcatenin protein was not due to increased expression of Bcatenin mRNA. These results suggest ICSBP influences expression of target genes involved in Bcatenin protein stability. Therefore, these studies identify a pathway by which Bcr/abl activity impairs ICSBP expression in immature myeloid cells, thereby increasing stability of Bcatenin protein and Bcatenin activity. Poor prognosis and BC are associated with Fas resistance and increased Bcatenin activity in CML leukemia stem cells (LSC). Bcr/abl activity is also associated with decreased expression of ICSBP. Our prior studies implicated ICSBP-deficiency in Fas-resistance in CML via the ICSBP target gene PTPN13. Our current studies implicate ICSBP-deficiency in increased Bcatenin expression in CML. These results suggest that decreased ICSBP expression drives multiple aspects of the poor prognosis LSC phenotype in CML.