Pickin, Anna (2017). Mechanistic insights into the effect of RUNX1/ETO knockdown in t(8;21) AML. University of Birmingham. Ph.D.
|
Pickin17PhD.pdf
PDF - Accepted Version Download (5MB) |
Abstract
The mutation of transcription factor genes is a main cause for acute myeloid leukaemia. RUNX1/ETO, the product of the t(8;21) chromosomal translocation, subverts normal blood cell development by impairing myeloid differentiation. RUNX1/ETO knockdown alleviates this block, with a global reprogramming of transcription factor binding and
initiation of myeloid differentiation. Co-depletion of the myeloid transcription factor C/EBPα with RUNX1/ETO suppressed this differentiation response. Furthermore, C/EBPα overexpression largely phenocopied the effect of RUNX1/ETO knockdown. Our data show that low levels of C/EBPα are critical to the maintenance of t(8;21) AML and that C/EBPα drives the response to RUNX1/ETO depletion.
To examine how changes in transcription factor binding impact on the activity of cisregulatory elements we mapped genome wide promoter-distal-element interactions in a
t(8;21) AML cell line, via Capture HiC, and found that hundreds of interactions were altered by RUNX1/ETO knockdown. Differentially interacting elements exhibited changes in C/EBPα binding and were enriched for the CTCF motif. Our results demonstrate that the presence or absence of RUNX1/ETO has a profound impact on the intra-nuclear organisation of t(8;21) AML cells, and indicate which transcription factors are driving these changes. This work provides a novel mechanism for the RUNX1/ETO mediated differentiation block in t(8;21) AML.
Type of Work: | Thesis (Doctorates > Ph.D.) | ||||||
---|---|---|---|---|---|---|---|
Award Type: | Doctorates > Ph.D. | ||||||
Supervisor(s): |
|
||||||
Licence: | |||||||
College/Faculty: | Colleges (2008 onwards) > College of Medical & Dental Sciences | ||||||
School or Department: | Institute of Biomedical Research | ||||||
Funders: | Cancer Research UK | ||||||
Subjects: | Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
||||||
URI: | http://etheses.bham.ac.uk/id/eprint/7160 |
Actions
Request a Correction | |
View Item |
Downloads
Downloads per month over past year