Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Molecular Cell Biology

Language

English (en)

Date of Award

January 2009

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Michael Tomasson

Abstract

ABSTRACT OF THE DISSERTATION Coordinate interstitial deletions of Retinoblastoma: RB1) and Neurobeachin: NBEA) genes on chromosome 13 in monoclonal gammopathy of undetermined significance: MGUS) and multiple myeloma By Julie O'Neal Doctor of Philosophy in Biology and Biomedical Sciences: Molecular and Cellular Biology) Washington University in Saint Louis, 2009 Assistant Professor Michael H. Tomasson, Chair Numeric or structural chromosomal abnormalities are detected in nearly all patients with plasma cell dyscrasias, including primary amyloidosis, monoclonal gammopathy of undetermined significance: MGUS) and multiple myeloma: MM). Chromosome 13 deletions, most frequently monosomy 13, are detected in 10- 20% of MM cases by routine cytogenetics or metaphase fluorescent in situ hybridization: FISH) and are a significant predictor of shortened survival. Previous efforts to map somatically acquired DNA copy number losses on chromosome 13 have been limited by their low resolution. To identify DNA copy number losses on chromosome 13 at high resolution, we used genomic DNA isolated from CD138 enriched bone marrow cells: tumor) from twenty patients xiv with MM, monoclonal gammopathy of undetermined significance: MGUS) or amyloidosis. We used matched skin biopsy: normal) genomic DNA to control for copy number polymorphisms and a novel aCGH array dedicated to chromosome 13 to map somatic DNA gains and losses at unprecedented resolution: >385,000 probes; median probe spacing 60bp). We identified RB1 and NBEA as being coordinately affected by copy number loss in MGUS and MM. To characterize these genes in the context of myeloma biology, we performed sequence and expression analysis on RB1 and found exonic mutations affecting RB1 were extremely rare, RB1 levels were decreased in patient samples harboring monosomy 13, and RB1 protein phosphorylation was not common. Expression analysis of NBEA revealed most patient samples harboring monosomy 13 had reduced NBEA, but to our surprise, a subset harbored high levels. Analysis of Nbea in hematopoietic tissues revealed although it was detected in thymus and spleen, using a fetal liver transplantation assay, Nbea was dispensable for hematopoietic development. Future studies investigating cooperation of RB1 and NBEA in plasma cell dyscrasias are warranted.

Comments

Permanent URL: http://dx.doi.org/10.7936/K75M63QX

Download

Share

COinS