First name
Elisa
Last name
Donato
Year of Study
Research Center
Thesis Title
Mechanistic investigation of BRD4 inhibition in MYC dependent tumors
Thesis Abstract
The c-myc gene encodes for a transcription factor involved in the regulation of different
cellular mechanisms, ranging from cell cycle control to cellular metabolism. Myc is
frequently altered in human cancer either by genomic rearrangement or by alteration of
upstream regulatory pathways. Myc crucial role both in tumor formation and maintenance
makes it an attractive molecular target for cancer therapy. Unfortunately, Myc is
intrinsically resilient to direct pharmacological targeting.
To overcome this issue, alternative therapeutic avenues have been explored. Independent
groups showed that BET proteins inhibition leads to a strong Myc downregulation in
Multiple Myelomas and Acute Myeloid Leukemias, with consequent cell cycle arrest and
tumor regression. Depending on c-myc location (translocated versus endogenous), two
different working models were proposed to explain BETi efficacy.
In order to improve our understanding of the mechanism of action of BETi, we evaluated
global transcriptional alteration and chromatin profiles in Burkitt’s Lymphomas in
response to JQ1.
Our results demonstrate that BETs inhibitors cause global alteration of RNA PolII
dynamics, due to the role of BRD4 in regulating elongation. Nonetheless, the selective
transcriptional effects following JQ1 treatment is due to promoter saturation and high
RNA PolII pausing that render the expression of JQ1 sensitive genes rate-limited by
transcriptional elongation. Indeed the same genes are selectively targeted by
pharmacological treatments affecting components of the elongation machinery. These
observations highlight the role of BETs protein in regulating gene expression and provide
a rationale to explain how broad inhibition of elongation may lead to a selective
transcriptional response.
cellular mechanisms, ranging from cell cycle control to cellular metabolism. Myc is
frequently altered in human cancer either by genomic rearrangement or by alteration of
upstream regulatory pathways. Myc crucial role both in tumor formation and maintenance
makes it an attractive molecular target for cancer therapy. Unfortunately, Myc is
intrinsically resilient to direct pharmacological targeting.
To overcome this issue, alternative therapeutic avenues have been explored. Independent
groups showed that BET proteins inhibition leads to a strong Myc downregulation in
Multiple Myelomas and Acute Myeloid Leukemias, with consequent cell cycle arrest and
tumor regression. Depending on c-myc location (translocated versus endogenous), two
different working models were proposed to explain BETi efficacy.
In order to improve our understanding of the mechanism of action of BETi, we evaluated
global transcriptional alteration and chromatin profiles in Burkitt’s Lymphomas in
response to JQ1.
Our results demonstrate that BETs inhibitors cause global alteration of RNA PolII
dynamics, due to the role of BRD4 in regulating elongation. Nonetheless, the selective
transcriptional effects following JQ1 treatment is due to promoter saturation and high
RNA PolII pausing that render the expression of JQ1 sensitive genes rate-limited by
transcriptional elongation. Indeed the same genes are selectively targeted by
pharmacological treatments affecting components of the elongation machinery. These
observations highlight the role of BETs protein in regulating gene expression and provide
a rationale to explain how broad inhibition of elongation may lead to a selective
transcriptional response.
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