Épissage alternatif et mutations ponctuelles de Pax5 chez la leucémie lymphoîde chronique et les lymphomes de cellules B

The transcription factor Pax5, or B-cell Specific Activator Protein (BSAP), possesses oncogenic properties and its expression is often deregulated in certain cases of B-cell malignancies such as non-Hodgkin lymphoma and acute lyrnphoblastic leukemia. Recent studies have revealed that the Pax5 transcript is subject to alternative splicing, thus producing multiple protein isoforms. Certain splicing events create a shift in the reading-frame and thus generate novel protein sequences, whereas other isoforms lack one or bath of the transactivation and inhibition domains of the original protein. It has become apparent that Pax5 related cancers are caused mostly by chromosomal translocations resulting in the over-expression or aberrant somatic hypermutation of the Pax5 gene, but recent studies have suggested the possibility that there is an altered modulation of human BSAP isoforms in certain B-cell cancers. This hypothesis is still very new, however, and has not been thoroughly explored. There are currently a growing number of human malignancies caused by aberrant splicing mechanisms. In the long mammalian introns, cryptic splice sites are kept silent by regulatory elements such as exonic and intronic splicing enhancers and silencers. Single nucleotide polymorphisms can affect these sites, thereby leading to aberrant splicing. In this context, we hypothesize that the deregulation of Pax5 isoforms in certain cancers results from a defective splicing mechanism. In this study, we sought to identify the Pax5 isoform expression profile of various B-cell lymphoma and chronic lymphocytic leukemia (CLL) patients in order to compare with the expression profile of normal B lymphocytes. In addition, pre-mRNA and mature Pax5 mRNA transcripts were amplified and sequenced in order to identify any recurrent mutations that might lead to the aberrant expression of isoforms of Pax5. Utilizing a high-resolution method of analyses of PCR products and immunodetection techniques, we have discovered that multiple isoforms of Pax5 are simultaneously expressed in normal B lymphocytes, as well as in B lymphocytes isolated from lymphoma and CLL patients. Further, we believe we have identified a "typical" expression pattern for isoforms in normal B lymphocytes. Contrary to our original hypothesis, we were unable to identify an obvious deregulation of Pax5 isoform expression in neither lymphoma nor CLL patients. We have, however, identified multiple polymorphisms expressed by Pax5 pre-mRNA transcripts in both leukemic and normal B cells, which could potentially affect its alternative splicing.

Name thesis:degree_name

Maîtrise ès sciences (biochimie)

Level thesis:degree_level

2e cycle

Discipline thesis:degree_discipline

Faculté des sciences

Grantor dc:publisher

Université de Moncton

Year dc:date.issued

2010

Author dc:creator

• Arseneau, Jean-René

Advisors dc:contributor.advisor

• Ouellette, Rodney
• Laflamme, Mark

• Facteurs de transcription
• Lymphocytes
• Transformation
• Lymphocytes B
• Leucémie lymphoïde chronique
• Épissage alternatif

Statement dc:rights

• Author

Language dc:language.iso

iso639-2b, fre

Identifier

oclc: 769769703

Dc Identifier Other

umir:1532

OAI identifier oai:identifier

oai:umoncton.scholaris.ca:20.500.14658/7212