Ricerca di contatti, progetti,
corsi e pubblicazioni

Sources of genomic instability in B cell malignancy

Persone

 

Robbiani D.

(Responsabile)

Bertoni F.

(Partner di progetto)

Abstract

Tumors of B lymphocytes often bear hallmark oncogenic chromosome translocations involving antibody genes, and the physiologically occurring breaks at these loci are thought to be a predisposing factor. However, breakage of antibody genes alone is insufficient for translocation, and the causes of fragility at the translocating partner genes remain largely unknown. We previously proposed that Activation-Induced cytidine Deaminase (AID), which physiologically remodels DNA at antibody genes in activated B cells, might be responsible for some of the aberrant DNA damage at cancer genes translocating in lymphoma. To test this hypothesis, we developed sensitive new tools and deep-sequencing methods to map chromosome damage and translocations that occur genome-wide, in primary cells, and in the absence of selection. This allowed us to discover that indeed AID causes collateral DNA damage at hundreds of specific genes in activated B cells, and that genome-wide DNA breaks by AID can lead to chromosome deletions and translocations, including some that are found in human B cell lymphoma. However, the fraction of cancer genes identified as AID targets is small in comparison to the full set of genes that are altered in B cell malignancy. Thus, the source of DNA damage at a majority of genes mutated or rearranged in leukemia and lymphoma remains elusive. B cells also express an anti-viral deaminase related to AID, Apolipoprotein B mRNA Editing enzyme Catalytic polypeptide-like 3 (APOBEC3). Although DNA mutations possibly mediated by APOBEC3 have been documented in some human B cell cancers, there is so far no genetic evidence that APOBEC3 contributes to lymphomagenesis. The overall aim of this proposal is to evaluate the contribution of APOBEC3 to the DNA damage leading to the genesis of B cell cancers. We hypothesize that APOBEC3 damages DNA at specific sites in the B cell genome causing chromosome rearrangements associated with lymphoma development. In Aim 1, we will examine the damage by APOBEC3 to the genome of primary mouse B lymphocytes and evaluate the effects of APOBEC3 deregulation on lymphoma development in murine models. In Aim 2, we will extend the investigations to human APOBEC3 and assess its role in shaping and promoting human B cell cancers. Research in this area is needed because many B cell cancers over-express APOBEC3 and therefore, if validated, this enzyme could become a target for therapeutic intervention. Moreover, APOBEC3 expression is not limited to B lymphocytes and mutational signatures consistent with APOBEC3 involvement are present in numerous non-hematopoietic malignancies as well. Therefore, the findings from our study may lead to broader impact beyond liquid tumors.

Informazioni aggiuntive

Data d'inizio
01.03.2021
Data di fine
28.02.2025
Durata
48 Mesi
Enti finanziatori
SNSF
Stato
In corso
Categoria
Swiss National Science Foundation / Project Funding / Division III - Biology and Medicine