Chromosomal locus 19p13 as potential hotspot for aberrant gene expression in relapsed paediatric acute lymphoblastic leukaemia

We read with interest the article by Beesley et al (2005), which reported the possible gene expression signature of relapse in paediatric pre-B acute lymphoblastic leukaemia (ALL). The authors analysed RNA extracted from 11 pairs of cryopreserved pre-B ALL bone marrow specimens taken from the same patients at diagnosis and relapse using Affymetrix HGU133A high-density oligonucleotide microarray. They showed that the relapse specimens overexpressed genes involved in cell growth and proliferation when compared with their diagnostic counterparts. Moreover, several chromosomal loci, including 19p13, were identified as potential hotspots for aberrant gene expression in relapsed ALL. To further explore the possibility of relapse prediction in paediatric pre-B ALL, we used a different approach, based on the hypothesis that ALL patients that will relapse already show a different expression profile in their leukaemic cells at the time of diagnosis from. To test this hypothesis, we compared leukaemic gene expression profiles in a set of 10 bone marrow samples obtained from ALL paediatric patients at the time of diagnosis. Four patients relapsed during therapy or early after stopping therapy and six are in continuous complete remission at 10 years from diagnosis. All of them share the following features: therapeutic protocol, prednisone good responder status, pre-B lineage, absence of chromosomal translocation and presence of >85% of blasts in the marrow. RNA was analysed by Affymetrix high-density oligonucleotide microarrays HG-U95Av2. Comparative analysis was performed using Affymetrix Microarray Suite 5Æ0 software algorithms (mas 5). Functional class and chromosomal loci were assigned using the NetAffx GO Mining Tool. We found that 39 genes were upregulated in relapsed patients. Analyses of their biological functions showed a predominance of genes involved in signal transduction, cell-cycle progression and regulation of transcription, suggesting impaired cell proliferation and apoptosis in B cell precursors of ALL relapsed patients. Moreover, among the 39 upregulated genes, six (15%) (NDUFB7, CD97, NDUFS7, BSG, ZNF91 and KCNN1) were localised in the chromosomal locus 19p13, which was found to be the most prevalent. A common finding in our study and that of Beesley et al (2005) was the recurrent upregulation of genes located in chromosomal locus 19p13 in diagnostic specimens of relapsed patients or in relapse specimens. This finding was also confirmed by Beesley et al (2005) in a separate analysis of the relapse data from Yeoh et al (2002). In particular, BSG, mapped on 19p13 locus, was a perfect marker for diagnosis and relapse specimens. It was significantly upregulated in the relapse specimen with respect to the diagnosis specimen as also reported by Yeoh et al (2002). In our samples, BSG was already overexpressed at diagnosis in the leukaemic cells of relapsed patients. This finding suggests that it could be a good predictor of relapse in paediatric pre-B ALL, and therefore the role of BSG expression in the mechanism of leukaemia relapse should be investigated further. A large amount of literature is available on the relationship between chromosomal locus 19p13 and cancer; in particular, translocations involving this locus are common in pre-B paediatric ALL (Pui et al, 2004) and an association with poor prognosis and response to therapy has also been reported (Khalidi et al, 1999). The diverse biological features of ALL patients analysed in these studies probably accounts for the variability of the data, but the common findings could be an interesting starting point to further investigate the potential role of 19p13 locus in the pathogenesis and prognosis of childhood ALL.