SEPT 6 Expression in Haematological Malignancy

 by  Hilary Russell  and  Peter Hall

An increasing body of data indicate that members of the septin gene family are implicated in human neoplasia.  For example SEPT9 lies at a locus that shows allelic imbalance in ovarian and breast cancer, is a target for retroviral insertional mutagenesis and is over-expressed in diverse human tumours and is a translocation partner for MLL in human leukaemia. 

SEPT6 is encoded by a gene on Xq24 and has also been implicated in leukaemia as a fusion partner of MLL.  We therefore investigated the genomic architecture, transcript profile, mRNA and protein expression of SEPT6.  The 12 exons of SEPT6 span 30 kbase and undergo complex splicing events.  We have defined these splicing events and report 7 distinct transcripts that encode 5 distinct polypeptides.  Of note are 3 discrete transcripts encoding the same 427 amino acid polypeptide: a phenomenon also seen with SEPT9.  We used a quantitative RT-PCR strategy to define the expression of these transcripts in cell lines and in fetal and adult tissues and show tissue specific patterns of expression. 

We took advantage of Affymetrix probe sets from sequences in exon 11a (212415_at), 11b (212413 _at, 212414 _at and 214298_x_at) and exon 12 (213666_at) and define SEPT6 mRNA expression in normal, diseased and neoplastic human tissues (n=10360).  The RT-PCR data validated the expression array and SEPT6 is expressed predominantly in lymphoid and CNS tissues.  These data are further substantiated by the use of anti-SEPT6 sera we generated that show that SEPT6 expression is high in these cell types.  SEPT6 protein is associated with the microtubule network and we have also identified a nuclear form of SEPT6 mediated by a bipartite NLS in the C terminus of SEPT6.  Finally we show that SEPT6 is over-expressed in lymphoid neoplasms.

Based upon these data we are now planning to investigate the expression of SEPT6 transcripts and proteins in a larger series of clinical samples  and investigate how SEPT6 protein contributes to the abnormalities in haematological malignancy.  This may lead to new insights into how these diseases develop, possible markers of disease that can be used to monitor patients and ultimately novel therapeutic options.