Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Microbiology and Immunology

Supervisor

Rodney DeKoter

Abstract

ETV6-RUNX1 is the most common chromosomal alteration in pediatric B cell acute lymphoblastic leukemia. ETV6-RUNX1 represses RUNX1 target genes. However, little is known about the target genes of ETV6-RUNX1 that are involved in promoting leukemogenesis. A recent study with two human leukemia cell lines AT-2 and REH, which express ETV6-RUNX1, suggested that SPIB was one of the top of the genes that were up regulated after knocking down the ETV6-RUNX1 fusion protein. In addition, our lab showed that deletion of PU.1 and Spi-B in B cells in mice resulted in the development of B cell acute lymphoblastic leukemia with 100% incidence. It is still not clear what pathways and target genes are affected by the loss of PU.1 and Spi-B and contribute to leukemogenesis. We hypothesized that ETV6-RUNX1 function as an oncogenic driver by repressing SPIB transcription, leading to impaired B cell receptor signaling. This hypothesis was divided into two parts. First, examining how PU.1 and Spi-B could act as tumor suppressor genes in B cells in our mouse model using gene expression profiling. The results of the microarray specified impairment in the expression of genes involved in BCR signaling pathways. Second, we aimed to determine the molecular mechanism of how SPIB is repressed by ETV6-RUNX1. ChIP results suggested that ETV6-RUNX1 directly interacts with SPIB. This study is expected to lead to a deeper understanding of the underlying biology of leukemogenesis caused by the loss of SPIB in ETV6-RUNX1 leukemia patients, hence allowing for the development of new molecular targeted therapies for B-cell leukemia

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