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c-myb alternative splicing: a novel biomarker in leukemia

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Please use this identifier to cite or link to this item: http://hdl.handle.net/1928/13191

c-myb alternative splicing: a novel biomarker in leukemia

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Title: c-myb alternative splicing: a novel biomarker in leukemia
Author: Zhou, Ye
Advisor(s): Ness, Scott
Committee Member(s): Ozben, Michelle
Hathaway, Helen
Edwards, Jeremy
Ness, Scott
Department: University of New Mexico. Biomedical Sciences Graduate Program
Subject: c-myb
alternative splicing
biomarker
next-generation sequencing
single molecule assay
Degree Level: Doctoral
Abstract: c-myb encodes a transcription factor that is essential for hematopoiesis and for normal development of other tissues. There is ample evidence showing the activated alleles of c-myb gene can induce leukemias in several animal species. However, there was no clear evidence showing that c-myb could be oncogenic in human cancers until recent studies revealed that the human c-myb locus is subjected to chromosomal rearrangement in some pediatric T-ALL and adenoid cystic carcinoma (ACC) patient samples. The c-myb gene contains 15 constant exons and 6 alternative exons and can undergo extensive alternative splicing. These alternatively spliced variants encode variant Myb proteins sharing the same DNA binding domain but distinct C-terminal domains. Evidence suggests that despite their identical DNA binding domains, these c-Myb variant proteins have unique transcriptional activities: the differences in the proteins allow the proteins to regulate different sets of target genes. Most importantly, some of the variants have C-terminal deletions that resemble the deletions in v-Myb, the oncogenic variant of c-Myb that can induce acute leukemias in chickens and mice. Previous studies showed that c-myb alternative splicing is tightly regulated during hematopoiesis. The profiles of c-myb alternative splicing in some leukemias are different from the profiles in normal bone marrow samples. We hypothesized that c-myb is a unique oncogene that is activated by alternative splicing in leukemias, resulting in the production of variant forms of c-Myb protein that contribute to hematopoietic cell transformation and the development of leukemia. To evaluate the clinical significance of c-myb alternative splicing and find out its correlation with leukemia, profiling of c-myb alternative splicing in a cohort of leukemia patient samples is needed. We developed a single-molecule exontyping method to characterize the alternative splicing of c-myb RNAs in a small cohort of pediatric pre-B-ALL samples and correlated the level or the pattern of c-myb splice variants with survival time of these patients. We detected that c-myb alternative splicing is more complex and more prevalent in leukemia patients than in normal cells. Furthermore, some splice variants encoding Myb proteins with truncations in the C-terminal domain are correlated with poor survival. We further explored the possibility of adapting high-throughput low-cost Next-Generation Sequencing methods to analyze c-myb alternative splicing at a large scale. We conclude that de-regulated c-myb alternative splicing could be an important contributor to the development of leukemia and that the analysis of c-myb splicing could provide a unique and novel approach of classifying leukemias, which is distinct from analyses performed with other technologies, such as microarray assays of gene expression.
Graduation Date: July 2011
URI: http://hdl.handle.net/1928/13191


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