Evaluating the pre-B-cell receptor as a potential mediator of leukemogenesis downstream of the TCF3-PBX1 oncogenic transcription factor
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Authors
Leblanc, Jesse
Date
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thesis
Language
eng
Keyword
TCF3-PBX1 , pre-B cell receptor signaling , Acute lymphoblastic leukemia
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Abstract
Approximately 5% of B-progenitor acute lymphoblastic leukemia (B-ALL) harbor a somatic 1;19 chromosomal translocation which generates a fusion gene coding for TCF3-PBX1. Recent studies have shown that leukemic progenitors with t(1;19) occur in a distinct subset of B-ALL cases that often express a functional pre-B-cell receptor (pre-BCR). It is hypothesized that TCF3-PBX1 drives the leukemogenesis of these cells by promoting aberrant pre-BCR signaling through transcriptional activation of genes encoding pre-BCR components (IGHM, CD79A, CD79B, IGLL1, VPREB1 and VPREB3). To test this hypothesis, we have established short hairpin RNA (shRNA) knockdown models in two different t(1;19) B-ALL cell lines (RCH-ACV and 697). Expression of the knockdown shRNA against the TCF3-PBX1 transcript considerably reduced cell culture-initiation and proliferation. We then performed RNA-Seq in both of our knockdown models and determined that TCF3-PBX1 knockdown surprisingly activates, rather than represses, the expression of IGHM, CD79A, CD79B, IGLL1, VPREB1 and VPREB3. Despite this, we observed a marked reduction in phosphorylation and activation of AKT and ERK in ¬TCF3-PBX1-silenced cells. Additionally, TCF3-PBX1 knockdown had no effect on SYK phosphorylation. Altogether, our results suggest that TCF3-PBX1 promotes t(1;19) B-ALL proliferation by activating PI3K/AKT and MAPK/ERK signaling in a pre-BCR independent manner. In considering alternative mechanisms by which TCF3-PBX1 promotes cell proliferation, TCF3-PBX1 activates the expression of genes encoding key downstream pre-BCR signaling molecules such as the Src-family kinase BLK and the atypical protein kinase C PKCζ either of which could promote pro-survival signaling pathways. Alternatively, we propose that TCF3-PBX1 promotes Notch or Rho signaling and that these pathways might crosstalk with the pre-BCR.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.