dc.description.abstract
The transcription factor MYC, encoded by the MYC gene, plays a central role in many
cellular processes, such as cell growth, apoptosis and cell communication. However,
as an oncogene, MYC also plays a central role in initiation and progression of many
different types of cancers, including malignant lymphomas, and is therefore the focus
of many oncological studies.
Malignant lymphomas do not refer to a single disease entity, but describe a broad
range of lymphatic neoplasias that derive from mature lymphoid cells. They can be
subclassified into over 60 subtypes based on their differentiation, morphology and/or
clinical course. Based on histology, malignant lymphomas can be generally
distinguished into Hodgkin's lymphoma (HL) and Non-Hodgkin's lymphoma (NHL).
NHL can be further sub-grouped according to their cell of origin into B- and T-cell NHL.
Further subclassification exists based on additional histological, clinical and molecular
criteria including chromosomal alterations and gene expression profiles. The present
work deals with Burkitt's lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL),
which both belong to aggressive high-grade B-cell lymphoma. Here, we explore the
role of the transcription factor MYC in the pathogenesis and clinical course of these
lymphoma types.
One hallmark of BL is the t(8;14) chromosomal translocation, leading to an
overexpression of MYC protein. MYC translocations are however, not restricted to BL,
but can also occur in DLBCL, although at a much lower frequency. MYC break-positive
BL differ significantly from the MYC break-positive DLBCL in their clinical course, with
BL associated with a complete cure of the majority of cases.
To investigate the molecular differences between these two lymphoma subtypes, we
performed a metabolic and proteomic study, identifying pyruvate as one of the
discriminatory metabolites. This metabolic phenotype was further confirmed by
proteomic studies of pyruvate metabolism-associated proteins (Schwarzfischer, et al.,
2017). In a second study, the genome-wide MYC binding pattern of BL, MYC breakpositive
and -negative DLBCL was analyzed by chromatin immunoprecipitation
followed by next generation sequencing (ChIP-Seq) and RNA-based next generation
sequencing (RNA-Seq). Significant differences in the MYC DNA-binding patterns were
identified, which were also mirrored in the different gene expression patterns. One of
these differentially expressed genes code for the cell surface receptor CD97 (ADGRE5), which is significantly over-expressed in BL, but absent in MYC breakpositive
and -negative DLBCL.
This finding was confirmed by independent validation experiments, including
immunohistological staining of cell lines and primary patient samples (Kleo et al 2018
– submitted).
This doctoral thesis was complemented by an investigation of long noncoding RNAs
(lncRNAs) and their role in modulating the MYC-driven cellular transcriptome. Using
NGS, we identified 13 lncRNAs, which were differentially expressed between BL and
DLBCLs, one of which was strongly regulated by MYC. This IncRNA was able to
modulate MYC-induced cell cycle genes with a strong impact on cell cycle progression.
We therefore called this lncRNA MINCR (MYC-induced non-coding RNA) (Doose, et
al., 2015).
Taken together, this thesis provides additional evidence that MYC is not merely an
on/off amplifier of gene activity but exerts specific actions on the gene expression
program and – as a consequence – on cellular functions, a finding also true for
aggressive lymphoma. Based on the MYC differences between BL and DLBCL, the
identification of biomarkers for their distinction appears to be possible. Therefore it is
justified to conclude that MYC plays an essential but diverse role in the pathogenesis
of various lymphoma types, a finding which might be important for future treatment
modalities.
The analyses of this work were partly conducted in cooperation with other research
groups and led to three publications, which provide the scientific basis for this
cumulative thesis.
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