Abstract 1500: The role of FUBP1 in the hematopoietic system and leukemia

Abstract

Abstract The transcriptional regulator FUBP1 (Far Upstream Element Binding Protein 1) acts as an oncoprotein in hepatocellular carcinoma (HCC) and is important for hematopoietic stem cell (HSC) self-renewal and erythroid maturation in mice. In this study, we investigated the transcriptional network by which FUBP1 controls hematopoiesis and elucidated the relevance of FUBP1 for human erythropoiesis. Furthermore, we shed light on the role of FUBP1 in leukemia initiating cells. Searching for upstream-regulators of FUBP1, we identified E-boxes as potential TAL1 binding sites in the FUBP1 promoter. Indeed, we demonstrated the regulation of FUBP1 expression by TAL1 in human primary CD34+ donor cells. In chromatin immunoprecipitation (ChIP) experiments, the binding of TAL1 to the FUBP1 promoter increased during erythroid differentiation, correlating with up-regulated FUBP1 and TAL1 expression. Activation of the FUBP1 promoter by TAL1 binding was confirmed in luciferase assays. We observed a reduction in erythroid colony-forming units and glycophorin A positive cells derived from erythroid differentiated human CD34+ cells upon knockdown of FUBP1, supporting the hypothesis that FUBP1 is required for efficient erythropoiesis. In the transduction/transplantation leukemia mouse models for BCR-ABL1+ CML and MLL-AF9+ AML, we observed that Fubp1 knockdown resulted in reduced total cell and progenitor cell numbers. In CML, Fubp1 knockdown cells showed lower cell cycle activity and increased apoptosis. Consistently, CML and AML mice transplanted with Fubp1 knockdown cells survived longer than control mice that received transduced bone marrow expressing wildtype FUBP1 levels. Furthermore, pharmacological treatment of AML mice with the FUBP1 inhibitor irinotecan prolonged their survival significantly as a single drug or in combination with Ara-C. Analysis of FUBP1 expression in bone sections derived from CML and AML patients, and from healthy donors by immunohistochemistry showed no increased FUBP1 expression in leukemic samples, but we noticed a shorter overall survival in those AML patients with strong FUBP1 expression. In CML patients, FUBP1 levels correlate with the disease stage. Thus, elevated expression of FUBP1 might be an indicator for the aggressiveness of leukemia. Our data identify TAL1 as an FUBP1 upstream-regulator and confirm the importance of FUBP1 for HSC self-renewal and erythroid maturation, not only in murine but also in human cells. Furthermore, FUBP1 acts as an oncogenic factor in leukemia. Our findings might provide important evidence for the potential use of FUBP1 in clinical settings, e.g. as a molecular target for the treatment of leukemia patients and as a modulator for the production of red cells. Citation Format: Marlene Steiner, Van T. Hoang, Jasmin Yillah, Katharina Gerlach, Jörn Lausen, Hans-Michael Kvasnicka, Thomas Oellerich, Hanibal Bohnenberger, Daniela Krause, Martin Zörnig. The role of FUBP1 in the hematopoietic system and leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1500.