Browsing by Subject "Acute Lymphoblastic Leukemia"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    B cell receptor signaling in receptor editing and leukemia.
    (2009-07) Ramsey, Laura Bailey
    There are many unanswered questions in the B cell field, but one of paramount importance is how B cells are tolerized to avoid autoimmunity. The majority of developing B cells are probably self-reactive, and many that make it through B cell development to the periphery show evidence of receptor editing. The question remains as to how the B cells signal to re-induce the editing machinery, whether it is a positive reactivation signal or the release of an inhibitory tonic signal. We propose that it is the release of a tonic signal through the B cell receptor that inhibits recombination when the BCR is present on the surface, but when the BCR binds self-antigen it is internalized, the inhibitory signal is abrogated, and the recombination machinery is reactivated. We tested this hypothesis using several transgenic models, including RAG2-GFP mice, HEL Ig mice, and anti-κ mice. We also used several mice deficient in BCR signaling to test this hypothesis, and found that reduced BCR signaling induces more receptor editing. When we tested mice with excessive BCR signaling or pharmacologically mimicked the BCR signal, we found a decrease in receptor editing. These experiments provide compelling evidence for the inhibitory tonic signaling hypothesis and against the activation signaling hypothesis. Another question unanswered in the B cell field is how B cells are transformed into leukemia and lymphoma. There have been whole genome analysis studies to show that genes involved in the BCR signaling pathway are involved in many B cell malignancies, including leukemia, lymphoma and myeloma. Our studies in mice provide evidence that in combination with constitutive STAT5 activation, a loss of genes involved in B cell development ( ebf1 and pax5 ) or pre-BCR signaling ( blnk, PKCβ, and btk ) results in leukemia. These are genes that have been shown to be deleted in B cell acute lymphoblastic leukemia (ALL). We also demonstrate an increase the phospho-STAT5 levels in adult BCR-ABL + ALL patients. Herein we have developed a new mouse model for B-ALL that may be useful in testing and perfecting treatment protocols used on ALL patients.
  • Thumbnail Image
    Item
    The balance of STAT5 and NFκB or IKAROS at enhancer networks dictates progenitor B cell survival, proliferation, and differentiation
    (2015-08) Katerndahl, Casey
    B cell Acute Lymphoblastic Leukemia (B-ALL) arises from transformation of progenitor B cells. The transcription factor STAT5 plays a critical role in B-ALL, as high STAT5 activation is correlated with poor patient survival. How STAT5 mediates this effect is unclear. Previous studies suggested that STAT5 simply promotes the survival of progenitor B cells. However, other roles for STAT5 in B-ALL have not been explored. This study demonstrates that STAT5 activation drives leukemia in cooperation with defects in a linear signaling pathway emanating from the pre-BCR, including Blnk, Btk, Prkcb, Nfkb1, and Ikaros. Using microarray analysis and chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq), we demonstrate that STAT5 antagonizes NFκB and IKAROS by opposing regulation of shared target genes. High levels of STAT5 binding was enriched at super-enhancers that are typically associated with an opposing network of B cell transcription factors including PAX5, EBF1, PU.1, IRF4, or IKAROS. The antagonism between STAT5 and NFκB or IKAROS has direct clinical relevance as the balance between these transcription factors affects patient outcome. Patients with high ratios of active STAT5 to NFκB or IKAROS have more aggressive disease characterized by decreased survival. Our studies illustrate how modest perturbations in two opposing transcriptional programs have dramatic consequences for B cell transformation, and that the degree of antagonism between these transcriptional programs correlates with patient survival.