Abstract

We previously showed that loss of function of the chromatin regulator polycomb group gene (PcG) eed increases susceptibility to lymphoid tumour development (Sauvageau, M. et al. Blood 104 (11); 213). The human eed locus is in a region of chromosome 11 (11q14.2–22.3) which is associated with recurrent deletions in several reported cases of lymphoproliferative diseases. The persistant expression of the wild-type allele of eed is maintained in lymphomas developing in eed+/− animals. This suggests a haploinsufficient function for this gene in preventing tumorigenesis. We recently exploited an insertional mutagenesis screen to identify new cooperative leukemia-inducing genes in eed mutant mice. 325 retroviral insertion sites (RIS) representing 189 different gene loci have been identified by inverse-PCR from a total of 51 lymphomas (25 eed−/− and 26 wild-type). This screen revealed 18 gene loci known to be cancer related and 21 new common insertion sites (CIS) such as sh2d3c (n=4 tumours), fgfr3 (n=15 tumours) and myo5b (n=7 tumours). More than 97% of these CIS were common to both eed mutant and wild-type animals. We next assessed the expression levels of all the genes found in a 100 Kb region of genomic DNA surrounding the CIS identified in our screen in eed mutant and wild-type tumours as well as in the corresponding non-leukemic tissues. Almost 17% of the 48 genes analyzed, including fgfr2, fgfr3, ttc16 and adam15, are aberrantly expressed in non-transformed eed mutant cells when compared to wild-type controls (levels 5–100+ fold). Importantly, several of these genes are either aberrantly expressed in wild-type and eed mutant tumours or represent true CIS thus indicating their possible contribution to early tumour development in eed mutant mice. Moreover, our results do not incriminate eed as a modifier of gene expression once cells are fully transformed, since the oncogenic complement is similar in eed mutant and wild-type leukemias. Collectively, our results link the haploinsufficient role of eed to the appropriate regulation of genes involved in leukemia development.

Author notes

Corresponding author