- Author
-
A.C. Leeksma
- Title
- Making sense of genomic complexity and nonsense-RNA in hematologic malignancies
- Supervisors
- Co-supervisors
-
J.E.J. Guikema
- Award date
- 18 October 2019
- Number of pages
- 194
- ISBN
- 9789463753432
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
The advent of novel efficacious but also expensive targeted agents has created an increased demand for more in-depth characterization and prognostication in chronic lymphocytic leukemia (CLL). Next-generation sequencing (NGS) analyses identified the splicing factor SF3B1 to be frequently mutated in cancer. Mutations in SF3B1 are characterized by increased expression of alternative transcripts. However, the pathobiological mechanism of these mutations is still unclear. This thesis aims to identify (i) the prognostic value of genomic aberrations and (ii) potential pathobiology of SF3B1 mutations in CLL and inhibition of the mRNA degradation pathway, nonsense-mediated decay (NMD), in hematologic malignancies. Studying large CLL patient groups using targeted-NGS within a comprehensive genomic profiling approach identified mutations not previously described in CLL. Additionally, clonal diversity was found to be predictive for adverse outcome. Genomic arrays were highlighted as an accurate diagnostic tool and identified high genomic complexity defined as five or more chromosomal aberrations detected by genomic arrays as an independent prognostic factor in CLL. Analysis of the functional effects of SF3B1 mutations revealed an intact TP53/ATM response in untreated SF3B1 mutated CLL cells, and SF3B1 mutation associated alternative transcripts appeared to be sensitive to NMD inhibition. Inhibition of the NMD regulator SMG1 was discovered as an exploitable clinical target with potent antitumor activity in a subset of tumors including multiple myeloma (MM). Finally, we identified biological correlates of response to SMG1 inhibition. Increased knowledge of splicing factors and NMD regulation will undoubtedly result in novel therapies.
- Persistent Identifier
- https://hdl.handle.net/11245.1/a211bfc9-f20d-429b-b850-b685ec64a442
- Downloads
-
Thesis (complete)
Front matter
Chapter 1: Introduction
Chapter 2: Clonal diversity predicts adverse outcome in chronic lymphocytic leukemia
Chapter 3: Genomic arrays identify high-risk chronic lymphocytic leukemia with genomic complexity: A multi-center study
Chapter 4: Functional analysis of the impact of SF3B1 mutations on the DNA damage response
Chapter 5: Effect of SF3B1 mutations on nonsense-mediated mRNA decay
Chapter 6: SMG1-mediated nonsense-mediated mRNA decay as therapeutic target in multiple myeloma
Chapter 7: Biological correlates of response to CC-115: Making sense of the nonsense-RNA related response
Chapter 8: General discussion
Summary; Samenvatting; Curriculum vitae; Publications; PhD portfolio; Dankwoord
Stellingen
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