Student Theses and Dissertations

Yair Dorsett

Date of Award

2008

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Nussenzweig Laboratory

Keywords

AID, c-myc translocation, Ig V-JH region, somatic hypermutation, miR-155, B cell lymphoma

Abstract

Chromosome translocations between oncogenes and the immunoglobulin (Ig) region spanning the variable (V), diversity (D) and joining (J) genes (Ig V-JH region) are found in a number of mature B cell lymphomas in humans and mice. The breakpoints are frequently adjacent to the recombination signal sequences (RSSs) targeted by recombinase activating genes 1 and 2 (RAG1/2) during antigen receptor assembly in pre- B cells, suggesting that these translocations might be the result of aberrant V(D)J recombination. However, in mature B cells undergoing AID dependent somatic hypermutation (SHM), duplications or deletions that would necessitate a double strand break make up 6% of all the Ig V-JH region associated somatic mutations. Furthermore, DNA breaks can be detected at this locus in B cells undergoing SHM. To determine whether SHM might induce c-myc to Ig V-JH translocations, we searched for such events in both IL6 transgenic (IL6 tg) and AID-/- IL6 tg mice. Our experiments demonstrate that AID is required for c-myc to Ig V-JH translocations induced by IL6. We also investigated the potential role of microRNAs (miRNAs) in AID mediated processes. MiRNAs are small non-coding RNAs that regulate vast networks of genes that share miRNA target sequences. To examine the physiologic effects of an individual miRNA in vivo we created a knock-in mouse that carries a mutation in the putative microRNA-155 (miR-155) target site in the 3'UTR of AID (AID155 mice). AID155 causes an increase in steady state AID mRNA and protein levels by increasing the half-life of the mRNA resulting in high levels of c-myc-IgH translocations. A similar but more pronounced translocation phenotype was also found in bic/miR-155 /- mice. Our experiments indicate that miR-155 can act as a tumor suppressor by reducing potentially oncogenic translocations generated by AID.

Comments

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy

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