ALBERT

Description: Abstract 3963 Poster Board III-899 Children with Down Syndrome (DS) have an increased risk of developing acute lymphoblastic leukemia (ALL). DS ALL patients differ in presenting characteristics from ALL patients without DS (non-DS ALL). Recent evidence suggests that a unique genetic event may characterize DS ALL, i.e. an activating mutation localized at R683 in the Janus Kinase 2 (JAK2) gene, which occurs in 18% of DS ALL cases, and differs from the JAK2 mutations that are typically found in Myeloproliferatieve diseases (Bercovich et al, The Lancet 2008). However, Mullighan et al. recently reported also JAK R683 mutations in non-DS high risk ALL (PNAS, 2009). Furthermore, we and others described deletions in B-cell development genes in high-risk ALL (Den Boer et al, Lancet Oncology 2009, and Mullighan, NEJM 2009). One of these genes, IKZF1, which encodes the lymphoid transcription factor IKAROS, was found to be an indicator of poor prognosis in this high-risk group. In the present study, we studied deletions in B-cell development genes in DS ALL, utilizing array-Comparative Genomic Hybridisation (array-CGH, 105K Agilent). Moreover, genomic DNA was PCR-amplified with specific primers to detect the isoform 6 of IKAROS, which consists of a deletion of exon 3-6 resulting in expression of a dominant-negative form of IKAROS, with intact homodimerization but reduced DNA-binding capacity. We used direct sequencing for mutation screening of the pseudo-kinase and kinase domains of JAK2. Of 34 DS ALL patients treated according to the DCOG treatment protocols samples were available. All 34 patients had B-cell precursor ALL. Median follow up time was 5.7 years (range 1.2 – 15.4 years).In total, 19/34 (56%) DS ALL patients had one or more deletions in B-cell development genes (Table 1). Affected genes included the transcription factors IKZF1 (41%, n=14), PAX5 (12%, n=4) and VPREB1 (18%, n=6). These aberrations were not mutually exclusive. No deletions were found in EBF1 and TCF3 (E2A). Deletions in the PAX5 gene were part of larger deletions (≥0.5 million bases), whereas the other genes were mainly affected by focal deletions (