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<p>Lymphomas comprise a diverse group of malignancies derived from immune cells.
High throughput sequencing has recently emerged as a powerful and versatile method
for analysis of the cancer genome and transcriptome. As these data continue to emerge,
the crucial work lies in sorting through the wealth of information to hone in on the
critical aspects that will give us a better understanding of biology and new insight
for how to treat disease. Finding the important signals within these large data sets
is one of the major challenges of next generation sequencing.</p><p>In this dissertation,
I have developed several complementary strategies to describe the genetic underpinnings
of lymphomas. I begin with developing a better method for RNA sequencing that enables
strand-specific total RNA sequencing and alternative splicing profiling in the same
analysis. I then combine this RNA sequencing technique with whole exome sequencing
to better understand the global landscape of aberrations in these diseases. Finally,
I use traditional cell and molecular biology techniques to define the consequences
of major genetic alterations in lymphoma.</p><p>Through this analysis, I find recurrent
silencing mutations in the G alpha binding protein GNA13 and associated focal adhesion
proteins. I aim to describe how loss-of-function mutations in GNA13 can be oncogenic
in the context of germinal center B cell biology. Using in vitro techniques including
liquid chromatography-mass spectrometry and knockdown and overexpression of genes
in B cell lymphoma cell lines, I determine protein binding partners and downstream
effectors of GNA13. I also develop a transgenic mouse model to study the role of
GNA13 in the germinal center in vivo to determine effects of GNA13 deletion on germinal
center structure and cell migration.</p><p>Thus, I have developed complementary approaches
that span the spectrum from discovery to context-dependent gene models that afford
a better understanding of the biological function of aberrant events and ultimately
result in a better understanding of disease.</p>
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