Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Microbiology and Immunology

Collaborative Specialization

Developmental Biology

Supervisor

DeKoter, Rodney P.

Abstract

The E26 transformation-specific transcription factors PU.1 and Spi-B are required for B cell maturation within the bone marrow. PU.1 expression is first detected in hematopoietic stem and progenitor cells, whereas Spi-B levels arise as early as the pro-B cell stage. The expression levels of both factors are maintained as B cells progress in development, and the lack of PU.1 and Spi-B at early stages impairs B cell development and can lead to B-cell leukemia. We hypothesized that PU.1 and Spi-B control events associated with the transition from high to low proliferative stages in B cell development and the absence of these factors favor a state of proliferative stress leading to leukemogenesis. To investigate this, we used a mouse model in which Spi1 was conditionally deleted in B cells by Cre recombinase under control of the Mb1 gene, in Spib deficient mice. We found PU.1 and Spi-B were required in B cell development during the transition from large to small pre-B cells. PU.1 functioned as an accessibility factor for immunoglobulin light chain rearrangement, enabling B cell maturation. We demonstrated that lack of Spi-B and PU.1 leads to B cell leukemia associated with driver mutations in the Janus Kinases genes 1 and 3 genes. Our data suggested that reactive oxygen species generation is a possible mechanism by which genetic damage arises consequently leading to B cell leukemia. This thesis contributes to the elucidation of molecular mechanisms by which the complementary transcription factors PU.1 and Spi-B coordinate B cell development and suppress leukemogenesis.

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