Abstract

We propose to use loss of heterozygosity studies and DNA sequencing to identify a gene at 13q14 that is involved in the pathogenesis of B-CLL. We have constructed and characterized a YAC contig spanning a region of 3 cM between the RB gene and the D13S31 locus. We have also screened 60 paired normal/tumor B CLL cases for allelic loss on chromosome 13 with 9 microsatellite markers in the region. This analysis has allowed us to narrow the smallest region of loss to a segment of 550 kb located between the 206XF12 and D13S25 markers. We have completed construction of a cosmid and BAC contig of the region and are carrying out exon trapping and cDNA selection experiments in order to identify candidate genes. We have also taken advantage of our outstanding automated DNA sequencing facility to sequence the entire 500 kb region. We have completed sequencing a 792 kb region that includes the minimal region of loss and are currently screening identified ESTs and ORFs in order to aid in the identification of the gene that is mutated and/or deleted in B-CLL.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA076259-03
Application #
6483403
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2001-05-01
Project End
2002-04-30
Budget Start
Budget End
Support Year
3
Fiscal Year
2001
Total Cost
Indirect Cost

  Institution

Name
Thomas Jefferson University
Department
Type
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107

  Publications

Thompson, Lorraine H; Whiston, Roy A; Rakhimov, Yerzhan et al. (2010) A LIF/Nanog axis is revealed in T lymphocytes that lack MARCH-7, a RINGv E3 ligase that regulates the LIF-receptor. Cell Cycle 9:4213-21
Almanza, Gonzalo; Fernandez, Antonio; Volinia, Stefano et al. (2010) Selected microRNAs define cell fate determination of murine central memory CD8 T cells. PLoS One 5:e11243
Garzon, Ramiro; Liu, Shujun; Fabbri, Muller et al. (2009) MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood 113:6411-8
Ghosh, Asish K; Shanafelt, Tait D; Cimmino, Amelia et al. (2009) Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cells. Blood 113:5568-74
Pufnock, Jeff S; Rothstein, Jay L (2009) Oncoprotein signaling mediates tumor-specific inflammation and enhances tumor progression. J Immunol 182:5498-506
Croce, Carlo M (2009) Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 10:704-14
Volinia, Stefano; Mascellani, Nicoletta; Marchesini, Jlenia et al. (2008) Genome wide identification of recessive cancer genes by combinatorial mutation analysis. PLoS One 3:e3380
Garzon, Ramiro; Garofalo, Michela; Martelli, Maria Paola et al. (2008) Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin. Proc Natl Acad Sci U S A 105:3945-50
Garzon, Ramiro; Volinia, Stefano; Liu, Chang-Gong et al. (2008) MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood 111:3183-9
Tili, Esmerina; Michaille, Jean-Jacques; Cimino, Amelia et al. (2007) Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol 179:5082-9

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