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8p11 myeloproliferative syndrome (EMS) is a clinical-pathologic entity characterized by rearrangements involving the FGFR1 gene, which encodes a receptor tyrosine kinase. These rearrangements invariably lead to aberrant fusion proteins in which the kinase activity is constitutively turned on, with resulting oncogenic properties. In this article, we describe a new translocation in EMS, t(7;8)(q34;p11), in which the FGFR1 gene is fused to a previously unidentified partner, the TIF1 gene. We show that both the TIF1-FGFR1 and FGFR1-TIF1 fusion proteins have the potential to be translated as a result of the translocation. Thus, our data extend the involvement of FGFR1 in EMS and lend support to the concept that there is a precise correlation between genotype and phenotype in this disease.

We performed a whole-genome loss of heterozygosity (LOH) analysis of 32 cases of acute myeloid leukemia with normal karyotype using high-density single nucleotide polymorphism arrays. LOH was found in 20% of cases. We identified two types of LOH: (i) interstitial, characterized by small deletions of genomic DNA (2-8 Mb), and (ii) terminal, involving large (30-90 Mb) telomeric regions. Surprisingly, terminal LOH occurred without loss of genetic material because of deletion of large chromosome regions and their substitution through the duplication of the corresponding regions from the homologous chromosomes (acquired partial uniparental disomy).

The stromal interaction molecular 1 gene (STIM1) encodes a type I trans-membrane protein of unknown function, which induces growth arrest and degeneration of the human tumor cell lines G401 and RD but not HBL100 and CaLu-6, suggesting a role in the pathogenesis of rhabdomyosarcomas and rhabdoid tumors. Here, we describe the STIM1 genomic organization including the identification of the promoter region. The gene consists of 12 exons that span a region larger than 250 kb between the genes RRM1 and NUP98. Nucleotide sequences of all exon-intron boundaries were determined and oligonucleotide primers for the amplification of individual exons were designed. The promoter region was identified within a 1.8-kb SacI fragment at the 5′ end of the gene. In vitro CpG methylation of the promoter region indicated that transcription can be downregulated by this mechanism. The genetic tools developed in the present work will help to determine whether pathogenetic mechanisms that associate STIM1 with tumorigenesis involve mutations in coding sequences and/or promoter, and whether methylation could determine STIM1 transcriptional down-regulation in tumor samples.

Six patients with de novo acute myeloid leukemia (AML) and a t(2;3)(p15-21;q26-27) were identified among approximately 1000 cases enrolled in the GIMEMA trial. The t(2;3) was the sole anomaly in three patients, whereas in three cases monosomy 7, trisomy 15 and 22, and trisomy 14 represented additional aberrations. No cryptic chromosome deletions at 5q, 7q, 12p, and 20q were observed. One patient carried a FLT3 D835 mutation; FLT3 internal tandem duplication (ITD) was not detected in three patients tested. Characterization of the translocation breakpoints using a 3q26 BAC contig specific for the PRDM3 locus showed that the breakpoints were located 5 0 to EVI1 as follows: within myelodysplatic syndrome (MDS) intron 1 (# 3), between MDS1 exons 2 and 3 in three patients (# 1, 2, 4) with a 170 bp cryptic deletion distal to the breakpoint in one (# 2), and in a more centromeric position spanning from intron 2 to the 5 0 region of EVI1 (# 6, 5). A set of 2p16-21 BAC probes showed that the breakpoints on chromosome 2p were located within BCL11A in two separate regions (# 1, 4 and # 2-5), within the thyroid adenoma-associated (THADA) gene (# 6) or distal to the ZFP36L2 locus (# 3). Regulatory elements were present in proximity of these breakpoints. RACE PCR studies revealed a chimeric transcript in 1/6 patient analyzed, but no fusion protein. Quantitative PCR showed a 21-58-fold overexpression of the EVI1 gene in all cases analyzed. The patients showed dysplasia of at least two myeloid cell lineages in all cases; they had a low-to-normal platelet count and displayed an immature CD34 þ CD117 þ immunophenotype. Despite intensive chemotherapy and a median age of 43 years (range 36-59), only two patients attained a short-lived response; one patient is alive with active disease at 12 months, five died at 4-14 months. We arrived at the following conclusions: (a) the t(2;3) is a recurrent translocation having an approximate 0.5% incidence in adult AML; (b) breakpoints involve the 5 0 region of EVI1 at 3q26, and the BCL11A, the THADA gene or other regions at 2p16.1-21; (c) cryptic deletions distal to the 3q26 breakpoint may occur in some cases; (d) the juxtaposition of the 5 0 region of EVI1 with regulatory elements normally located on chromosome 2 brings about EVI1 overexpression; (e) clinical outcome in these cases is severe.

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A detailed long range restriction map of the region de®ned by markers D6S149 and D6S193 on chromosome 6q27 has been constructed. This was achieved by YAC cloning and contig assembling of the same region. Seven YAC clones were found to span the almost 1000 Kb region¯anked by the two markers which on the genetic map resulted to be 1.9 cM apart. With some of the characterized YAC clones we undertook a molecular cytogenetic analysis of 20 benign ovarian tumors. The rationale for this was the recent mapping to a region of chromosome 6q27,¯anked by markers D6281 and D6S133, of a locus for the SV40-mediated immortalization of human cells (SEN6 gene). Noteworthy we found that the the D6S149-D6S193 region (comprised in the larger D6S281-D6S133 physical interval) was altered in all samples analysed adding support to the occurrence of a immortalization step in this type of tumors.

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