Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Ingo Ringshausen, University College London, UK
- Second opponent: Associate Professor Helene Hallböök, Uppsala University, Sweden
- Third member and chair of the evaluation committee: Associate Professor Lorena Arranz, University of Oslo
Chair of the Defence
Professor Emeritus Inger Sandlie, University of Oslo
Principal Supervisor
Associate Professor Hilde Schjerven, University of Oslo
Summary
B – acute lymphoblastic leukemia (B-ALL) is a malignancy of immature B cells starting in the bone marrow and subsequently spreading into the blood and other organs. B-ALL is characterized by a variety of genomic aberrations that make it challenging to treat. Sequencing technologies have dissected the genomic landscape of B-ALL, leading to tremendous progress in patient stratification and targeted therapies. Despite these advancements, the cure rate for adults over 40 with B-ALL remains 40%, urging for better risk stratification and newer therapies.
This thesis explores the potential of RNA sequencing in improving patient risk stratification, identifying new biomarkers and therapeutic targets to improve diagnosis and treatment choices. We performed RNA-Seq on an adult B-ALL patient cohort followed by a varied analysis for an in-depth molecular diagnosis of these patients. Through fusion analysis we found common genomic lesions such as BCR-ABL, CRLF2 and DUX4 which went undetected by standard diagnostic tests. Additionally, we found novel genomic fusions such as P2R8Y-IgH, which is currently not included in the standard diagnostic tests. Another finding of RNA- seq analysis was the identification of recurrent SNVs in NRAS and KRAS genes, commonly seen in other cancers, as well as the R683G mutation in Jak2 gene, which can already be targeted through inhibitors. Lastly as a RNA-Seq analysis, we performed a differential gene expression analysis on our RNA-Seq data and found CCR6, a novel biomarker expressed on 2 distinct subtypes of B-ALL.
We followed up on our RNA-Seq findings by validating the expression of our biomarker on a protein level through flow cytometry. We also performed an in vitro study assessing the therapeutic potential of several inhibitors in B-ALL, showing promising results.
In conclusion, these findings show that the use of RNA-Seq improves clinical diagnostics of B-ALL through identifying new biomarkers and finding novel and overlooked fusions by standard diagnostic tests. Additionally, RNA-Seq can guide treatment choices by discovering already targetable mutations, offering new treatment options.
Additional information
Contact the research support staff.