DeKoter Lab

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Research Projects

The long-term goal of our research is to determine the molecular mechanisms that underlie blood diseases.  In particular, we are studying the role of transcription factor proteins in immune deficiency and leukemia.

Regulation of B cell development and function by Ets family transcription factors.  Our laboratory is working to elucidate the role of E26 transformation-specific (Ets) family transcription factors in B cells. We have recently investigated the function of PU.1, as well as two closely related Ets family members called Spi-B and Spi-C. PU.1 and Spi-B activate transcription of genes encoding several mediators of B cell receptor (BCR) signaling. Our experiments suggest that Spi-C opposes the activity of PU.1 and Spi-B in vitro and in vivo. Spi-C is expressed at stages of B cell development in which BCR signaling induces anergy or death rather than activation. Our long-term goal is to determine the roles of PU.1, Spi-B, and Spi-C in antibody formation and autoimmune disease.

Transcriptional regulation of normal and leukemic hematopoiesis.  Generation of blood cells from the hematopoietic stem cell (HSC) is regulated by a fine balance between proliferation and differentiation. Tipping of this balance toward excessive proliferation can lead to leukemia. The Ets family transcription factors PU.1 and Spi-B are pivotal in regulating both proliferation and differentiation of HSCs. Mutation or repression of the gene encoding PU.1 (SPI1 in human and Spi1 in mice) has been shown to be involved in the development of human acute myeloid leukemia (AML) and pediatric B cell acute lymphoblastic leukemia (B-ALL). It is not known how downstream target genes sense and interpret changes in PU.1/Spi-B concentration. During the last three years my laboratory has generated novel in vivo and in vitro model systems that will allow us to address these important questions. Mice homozygous for a hypomorphic allele of PU.1 (Sfpi1BN/BN) express ~20% of wild type PU.1 protein levels and develop AML. Mice that delete PU.1 during B cell development, and are homozygous null for Spi-B (Mb1CreSpi1lox/loxSpib-/-), develop B-ALL by 18-20 weeks of age. We are currently using ChIP-seq and whole exome sequencing to determine how reduced PU.1/Spi-B predispose developing hematopoietic cells to malignancy.

Metabolic regulation of cell cycle in the myeloid lineage.  There is emerging evidence that metabolic changes during hematopoietic development are an important input into control of the cell cycle clock. A long-term goal of this research program is to determine how metabolic changes, cell cycle, and terminal differentiation are coordinated by cell type-specific transcription factors such as PU.1. We expect that determining how PU.1 controls cellular metabolism and cell cycle status will provide important insight into the biology of myeloid differentiation.