Discovery and Functional Interrogation of Biomarkers Related to Therapeutic Response in Chronic Lymphocytic Leukemia.
Year: 2017
Type: article
Study design: Observational Study
Abstract: Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the United States.CLL is a highly heterogeneous disease; patients may progress within months or live out their lives without requiring intervention.As most patients are asymptomatic and early stage at diagnosis, biomarkers are key to predicting outcomes for these patients.Biomarkers are cellular, biochemical or molecular alterations that are measureable indicators of disease processes or pharmacological responses.The work presented here focuses on identification of novel biomarkers for CLL.Chapter one provides background on CLL and describes biomarkers as well as therapeutics currently in use for this disease.Chapter two describes a novel chromosomal abnormality in CLL, the jumping translocation.We found that this abnormality contributed to patients acquiring the aggressive disease markers, complex karyotype and deletion of 17p.Chapter three interrogates the ability of two chromosomal markers, gain of 2p and tetraploidy, to predict for progression on the Bruton's tyrosine kinase inhibitor, ibrutinib.While gain of 2p showed a trend of increased occurrence in patients who later progressed, it was not a statistically significant predictor for progression.On the other hand, tetraploidy was highly enriched in patients who progressed on ibrutinib through Richter's transformation, a transformation to an aggressive lymphoma.Being positive for tetraploidy prior to receiving ibrutinib was significantly associated with progression iii through Richter's transformation.Chapter four is focused on the discovery of aberrantly expressed long noncoding RNA (lncRNA) in CLL.LncRNAs are non-protein coding transcripts greater than 200 nucleotides in length.Recent studies have elucidated transcriptional and translational regulatory roles for some of these molecules.We identified a lncRNA, named treRNA, which was associated with aggressive disease markers and was an independent predictor of progression free response on the chemotherapeutic combination of fludarabine and cyclophosphamide.We found enforced expression of treRNA in a CLL cell line resulted in decreased DNA damage when exposed to these agents.Chapter five discusses conclusions and future directions for this work.Together, this work describes several novel biomarkers for CLL.This work adds to our ability to predict for disease aggressiveness and therapeutic response in CLL.Furthermore, by identifying these markers we have uncovered novel avenues for interrogation of the biology of this disease.iv Dedication To David….you have my heart.
Author: Cecelia Miller
Institution: The Ohio State University
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2604000411