Download the full-sized PDF of Deregulation of DNA mismatch repair by the oncogenic tyrosine kinase NPM-ALKDownload the full-sized PDF



Permanent link (DOI):


Export to: EndNote  |  Zotero  |  Mendeley


This file is in the following communities:

Graduate Studies and Research, Faculty of


This file is in the following collections:

Theses and Dissertations

Deregulation of DNA mismatch repair by the oncogenic tyrosine kinase NPM-ALK Open Access


Other title
mismatch repair
Type of item
Degree grantor
University of Alberta
Author or creator
Bone, Kathleen M
Supervisor and department
Lai, Raymond (Laboratory Medicine and Pathology)
Examining committee member and department
Fu, Yangxin (Oncology)
Murray, David (Oncology)
Andrew, Susan (Medical Genetics)
Keelan, Monika (Laboratory Medicine and Pathology)
Jirik, Frank (Biochemistry and Molecular Biology)
Laboratory Medicine and Pathology

Date accepted
Graduation date
Doctor of Philosophy
Degree level
The vast majority of anaplastic lymphoma kinase positive anaplastic large cell lymphoma (ALK+ALCL) tumors carry the genetic translocation t(2;5)(p23;q35), leading to production of the constitutively active fusion tyrosine kinase NPM-ALK. NPM-ALK expression and its potent transformative properties are central to the pathogenesis of this disease. The Lai Laboratory recently identified MSH2, an integral component of the DNA mismatch repair (MMR) pathway, as a novel NPM-ALK interactor by mass spectrometry. DNA MMR proteins aid in tumor suppression through the maintenance of genomic instability, and their loss is highly oncogenic. As NPM-ALK is a tyrosine kinase that binds to and phosphorylates downstream proteins to mediate its tumorigenesis, it was hypothesized that through its interaction with MSH2, NPM-ALK interferes with its biological function, impacting MMR. The major findings of this study are that NPM-ALK indeed binds and tyrosine phosphorylates MSH2, blocking the interaction with its main MMR binding partner, MSH6, and inducing cytoplasmic retention of MSH2 in the presence of DNA damage. Correlating with these findings, ALK+ALCL patient samples displayed evidence of MMR dysfunction, including accentuated MSH2 cytoplasmic staining, and microsatellite instability. Furthermore, tyrosine 238 in the MSH2 protein was identified as the key NPM-ALK-induced tyrosine phosphorylation site in the context of MMR deregulation; overexpression of a non-phosphorylatable mutant, MSH2Y238F, in NPM-ALK expressing cell lines reversed MSH2 tyrosine phosphorylation, and restored the interaction of MSH2 and MSH6, resulting in a return of MMR function. Finally, using a novel antibody specifically designed against phosphorylated MSH2 at tyrosine 238, other clinically relevant oncogenic tyrosine kinases were found to interact with MSH2, inducing its phosphorylation at tyrosine 238, leading to MMR dysfunction. This is the first reported evidence of post-translational modification of MSH2 at a specific residue, tyrosine 238, by oncogenic tyrosine kinases with a direct impact on MMR function. Altogether, this study provides novel insights into the deregulation of DNA repair by oncogenic tyrosine kinases, with widespread implications for tyrosine kinase screening and targeted cancer therapy.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Young LC, Bone KM, Wang P, Wu F, Adam BA, Hegazy S, Gelebart P, Holovati J, Li L, Andrew SE, Lai R. Fusion tyrosine kinase NPM-ALK deregulates MSH2 and suppresses DNA mismatch repair function: novel insights into a potent oncoprotein. American Journal of Pathology. 2011. Jul; 179(1):411-421.

File Details

Date Uploaded
Date Modified
Audit Status
Audits have not yet been run on this file.
File format: pdf (PDF/A)
Mime type: application/pdf
File size: 32992903
Last modified: 2015:10:12 15:43:29-06:00
Filename: Bone_Kathleen_M_201409_PhD.pdf
Original checksum: 7b0abbc0468874c77ba94753373eeb2b
Activity of users you follow
User Activity Date