The transcription factor c-Maf is upregulated in hematopoietic stem cells of PU.1 knockdown mice which develop acute myeloid leukemia (AML). In another hematologic malignancy, multiple myeloma, c-Maf functions as an oncogene, contributing to the accumulation of malignant cells. Here we hypothesize that c-Maf is an important regulator of normal stem cells and a critical oncogenic target in AML induced by knockdown of the transcriptional master regulator PU.1. To test this hypothesis we will explore the consequences of c-Maf loss- of-function and gain-of-function in normal and malignant hematopoietic stem (HSC) and progenitor cells, as well as the mechanism through which c-Maf contributes to the pathogenesis and maintenance of leukemia stem cells. Strategies employed will include both biochemical and functional experiments. Biochemical assays such as Electrophoretic Mobility Shift Assay, Chromatin Immunoprecipitation, promoter-reporter assays and targeted mutagenesis, will be used to address the relationship between PU.1 knockdown and the upregulation of c-Maf, and to confirm whether c-Maf is a direct transcriptional target of PU.1. Meanwhile, in vitro and in vivo functional assays will help examine the importance of c-Maf in normal stem cell and leukemic stem cell development. Understanding the role c-Maf plays in AML can provide the basis for novel therapeutic approaches that aim at directly targeting c-Maf in the leukemia stem cell population. Relapses, which are very frequent in AML patients, are believed to occur as a consequence of the survival of these leukemia initiating cells;hence, by specifically targeting this population of malignant cells, we believe that this approach can lead to lasting cures of the disease and overall improvement in patient outcome.
The goal of this project is to understand the mechanism and role of c-Maf deregulation in hematopoietic stem and progenitor cells and in leukemia. In order to characterize the function of c-Maf in normal hematopoietic stem and progenitor cells, as well as in the pathogenesis of Acute Myeloid Leukemia (AML), we will conduct biochemical and functional assays. Through these experiments and analysis we can confirm whether c-Maf is a direct transcriptional target of the myeloid master regulator and stem cell tumor suppressor PU.1 and possibly elucidate a novel therapeutic approach at targeting the leukemia stem cell population in the hopes of providing a lasting cure.
|Will, Britta; Vogler, Thomas O; Bartholdy, Boris et al. (2013) Satb1 regulates the self-renewal of hematopoietic stem cells by promoting quiescence and repressing differentiation commitment. Nat Immunol 14:437-45|