Acute myeloid leukemia (AML) is one of the most common leukemias with a 20% 5-year event-free survival in adults and 50% overall survival in children, despite aggressive chemotherapy treatment and bone marrow transplantation. The incidence and mortality rates for acute leukemia have only slightly decreased over the last 20 years and therefore greater understanding of the molecular mechanisms associated with leukemic progression is needed. To this end, a number of transcription factors which appear to play a central role in leukemogenesis are being investigated; among them is the cAMP response element binding protein (CREB). CREB is a transcription factor that can regulate downstream targets involving in various cellular functions including cell proliferation, survival, and differentiation. In several studies, the majority of bone marrow samples from patients with acute lymphoid and myeloid leukemia demonstrate CREB overexpression. Moreover, CREB overexpression is associated with a poor outcome in AML patients. This review summarizes the role of CREB in leukemogenesis.
The cAMP response element-binding protein (CREB) is a nuclear transcription factor that is critical for normal and neoplastic hematopoiesis. Previous studies have demonstrated that CREB is a proto-oncogene whose overexpression promotes cellular proliferation in hematopoietic cells. Transgenic mice that overexpress CREB in myeloid cells develop a myeloproliferative disease with splenomegaly and aberrant myelopoiesis. However, CREB overexpressing mice do not spontaneously develop acute myeloid leukemia. In this study, we used retroviral insertional mutagenesis to identify genes that accelerate leukemia in CREB transgenic mice. Our mutagenesis screen identified several integration sites, including oncogenes Gfi1, Myb, and Ras. The Sox4 transcription factor was identified by our screen as a gene that cooperates with CREB in myeloid leukemogenesis. We show that the transduction of CREB transgenic mouse bone marrow cells with a Sox4 retrovirus increases survival and self-renewal of cells in vitro. Furthermore, leukemic blasts from the majority of acute myeloid leukemia patients have higher CREB, phosphorylated CREB, and Sox 4 protein expression. Sox4 transduction of mouse bone marrow cells results in increased expression of CREB target genes. We also demonstrate that CREB is a direct target of Sox4 by chromatin immunoprecipitation assays. These results indicate that Sox4 and CREB cooperate and contribute to increased proliferation of hematopoietic progenitor cells.
Central to discovering novel approaches to treating leukemias and lymphomas is a clear understanding of the signaling networks which lead to unchecked cell cycle progression, proliferation, and survival. Cyclic-adenosine monophosphate (cAMP) responsive element-binding protein (CREB) represents a critical integrator of numerous signals from cytoplasmic kinase cascades, and is directly involved in controlling the transcription of genes critical for normal cellular proliferation and survival. Several lines of evidence implicate CREB as a proto-oncogene, as a number of translocations involving CREB and dysregulation of expression are both associated with oncogenesis. Thus, CREB represents a potential therapeutic target in leukemia. Here, we review CREB function and regulation in normal and aberrant hematopoiesis.
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