On 13q14 deletions in chronic lymphocytic leukemia
Author: Lerner, Mikael
Date: 2008-06-13
Location: Cancer Centrum Karolinskas föreläsningssal, entréplan, Karolinska Universitetssjukhuset, Solna
Time: 09.00
Department: Institutionen för onkologi-patologi / Department of Oncology-Pathology
View/ Open:
Thesis (1.273Mb)
Abstract
Malignant tumors arise as a consequence of a multistep process where an accumulation of genetic and epigenetic changes drives the transformation of normal cells into tumor cells. The identification and characterization of genes targeted by these alterations is of crucial importance for an increased understanding of the biology of cancer.
The studies in this thesis have focused on genetic aberrations in chronic lymphocytic leukemia (CLL), and specifically those affecting chromosome band 13q14.3. Deletions involving 13q14 occur in more than 50% of all CLL cases and loss of this locus is also observed in several other malignancies. Results from numerous previous studies have indicated that a segment containing the DLEU2 and RFP2/LEU5 genes is targeted by these deletions. We characterized these genes with the purpose of elucidating the driving force behind these changes.
The RFP2/LEU5 gene is the only protein-coding gene in the region. We demonstrated that Rfp2 is a novel RING E3 ubiquitin ligase. A series of experiments furthermore established Rfp2 as a membrane-bound protein specifically involved in endoplasmic reticulum-associated degradation (ERAD), a process responsible for the clearance of misfolded and improperly assembled proteins from the endoplasmic reticulum.
Characterization of DLEU2 allowed us to demonstrate that it functions as a regulatory host gene for the microRNAs miR-15a and miR-16-1. These microRNAs were shown to target the G1 cyclins D1 and E1 for translational repression. In line with this, ectopic expression of DLEU2, and hence also miR-15a/miR-16-1, inhibited the colony-forming ability of tumor cell lines. Finally, we demonstrated that DLEU2 is transcriptionally regulated by the oncoprotein Myc that associates with and represses the two alternative DLEU2 promoters. Together, our data strongly support an important function for DLEU2 in regulation of G1 cyclin protein levels and further suggest a novel mechanism for Myc-induced proliferation. In this way, inactivation of DLEU2 could promote G1 cyclin deregulation and tumor progression.
In another study, we investigated the underlying molecular mechanism behind genomic aberrations in CLL. By analyzing genetic breakpoints from CLL patients, we could identify a CLL-specific signature. Our studies revealed that CLL breakpoints are characterized by an overrepresentation of short direct repeats, a feature not found in other malignancies analyzed. This indicates that repeats of this kind are specifically involved in genetic recombination leading to deletions and translocations in CLL. The results presented in this thesis provide insight into the nature of genetic alterations in CLL, and specifically help define the molecular basis of 13q14.3 aberrations in malignancy.
The studies in this thesis have focused on genetic aberrations in chronic lymphocytic leukemia (CLL), and specifically those affecting chromosome band 13q14.3. Deletions involving 13q14 occur in more than 50% of all CLL cases and loss of this locus is also observed in several other malignancies. Results from numerous previous studies have indicated that a segment containing the DLEU2 and RFP2/LEU5 genes is targeted by these deletions. We characterized these genes with the purpose of elucidating the driving force behind these changes.
The RFP2/LEU5 gene is the only protein-coding gene in the region. We demonstrated that Rfp2 is a novel RING E3 ubiquitin ligase. A series of experiments furthermore established Rfp2 as a membrane-bound protein specifically involved in endoplasmic reticulum-associated degradation (ERAD), a process responsible for the clearance of misfolded and improperly assembled proteins from the endoplasmic reticulum.
Characterization of DLEU2 allowed us to demonstrate that it functions as a regulatory host gene for the microRNAs miR-15a and miR-16-1. These microRNAs were shown to target the G1 cyclins D1 and E1 for translational repression. In line with this, ectopic expression of DLEU2, and hence also miR-15a/miR-16-1, inhibited the colony-forming ability of tumor cell lines. Finally, we demonstrated that DLEU2 is transcriptionally regulated by the oncoprotein Myc that associates with and represses the two alternative DLEU2 promoters. Together, our data strongly support an important function for DLEU2 in regulation of G1 cyclin protein levels and further suggest a novel mechanism for Myc-induced proliferation. In this way, inactivation of DLEU2 could promote G1 cyclin deregulation and tumor progression.
In another study, we investigated the underlying molecular mechanism behind genomic aberrations in CLL. By analyzing genetic breakpoints from CLL patients, we could identify a CLL-specific signature. Our studies revealed that CLL breakpoints are characterized by an overrepresentation of short direct repeats, a feature not found in other malignancies analyzed. This indicates that repeats of this kind are specifically involved in genetic recombination leading to deletions and translocations in CLL. The results presented in this thesis provide insight into the nature of genetic alterations in CLL, and specifically help define the molecular basis of 13q14.3 aberrations in malignancy.
List of papers:
I. Corcoran MM, Hammarsund M, Zhu C, Lerner M, Kapanadze B, Wilson B, Larsson C, Forsberg L, Ibbotson RE, Einhorn S, Oscier DG, Grandér D, Sangfelt O (2004). DLEU2 encodes an antisense RNA for the putative bicistronic RFP2/LEU5 gene in humans and mouse. Genes Chromosomes Cancer. 40(4): 285-97
Pubmed
II. Lerner M, Corcoran M, Cepeda D, Nielsen ML, Zubarev R, Pontén F, Uhlén M, Hober S, Grandér D, Sangfelt O (2007). The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin ligase involved in ERAD. Mol Biol Cell. 18(5): 1670-82. Epub 2007 Feb 21
Pubmed
III. Lerner M, Harada M, Loven J, Castro J, Henriksson M, Sangfelt O, Grander D, Corcoran MM (2008). DLEU2 downregulates the G1 Cyclins D1 and E1 through microRNA-mediated repression. [Submitted]
IV. Lerner M, Enge M, Farnebo M, Ibbotson RE, Gardiner A, Merup M, Oscier DG, Selivanova G, Grander D, Corcoran MM (2008). Analysis of chronic lymphocytic leukemia breakpoints implicates short direct repeats as a disease-specific cause of double strand break formation. [Submitted]
I. Corcoran MM, Hammarsund M, Zhu C, Lerner M, Kapanadze B, Wilson B, Larsson C, Forsberg L, Ibbotson RE, Einhorn S, Oscier DG, Grandér D, Sangfelt O (2004). DLEU2 encodes an antisense RNA for the putative bicistronic RFP2/LEU5 gene in humans and mouse. Genes Chromosomes Cancer. 40(4): 285-97
Pubmed
II. Lerner M, Corcoran M, Cepeda D, Nielsen ML, Zubarev R, Pontén F, Uhlén M, Hober S, Grandér D, Sangfelt O (2007). The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin ligase involved in ERAD. Mol Biol Cell. 18(5): 1670-82. Epub 2007 Feb 21
Pubmed
III. Lerner M, Harada M, Loven J, Castro J, Henriksson M, Sangfelt O, Grander D, Corcoran MM (2008). DLEU2 downregulates the G1 Cyclins D1 and E1 through microRNA-mediated repression. [Submitted]
IV. Lerner M, Enge M, Farnebo M, Ibbotson RE, Gardiner A, Merup M, Oscier DG, Selivanova G, Grander D, Corcoran MM (2008). Analysis of chronic lymphocytic leukemia breakpoints implicates short direct repeats as a disease-specific cause of double strand break formation. [Submitted]
Issue date: 2008-05-23
Rights:
Publication year: 2008
ISBN: 978-91-7409-067-3
Statistics
Total Visits
Views | |
---|---|
On ...(legacy) | 651 |
On ... | 123 |
Total Visits Per Month
September 2023 | October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | |
---|---|---|---|---|---|---|---|
On ... | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
File Visits
Views | |
---|---|
thesis.pdf(legacy) | 450 |
thesis.pdf | 162 |
thesis.pdf.txt(legacy) | 2 |
Top country views
Views | |
---|---|
United States | 330 |
Sweden | 79 |
China | 74 |
Germany | 51 |
Russia | 20 |
South Korea | 17 |
Finland | 14 |
Denmark | 10 |
United Kingdom | 7 |
Ireland | 7 |
Top cities views
Views | |
---|---|
Romeo | 36 |
Beijing | 33 |
Sunnyvale | 26 |
Kiez | 23 |
Seoul | 14 |
Stockholm | 11 |
Helsinki | 8 |
Ballerup | 6 |
Dublin | 6 |
London | 6 |