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The genetic landscape of T-ALL has been very actively explored during the past decades. This leads to an overwhelming body of exciting novel findings providing insight into (1) the genetic heterogeneity of the disease with marked genetic subsets, (2) the mechanisms by which aberrant T-cell development drive leukemogenesis and (3) emerging opportunities for novel therapeutic interventions. Of further interest, recent genome wide sequencing studies identified proteins that actively participate in the regulation of the T-cell epigenome as novel oncogenes and tumor suppressor genes in T-ALL. The identification of these perturbed molecular epigenetic events in the pathogenesis of T-ALL will contribute to the further exploration of novel therapies in this cancer type. As some epigenetic therapies have recently been approved for a number of hematological neoplasms, one could speculate that targeted therapies against epigenetic regulators might offer good prospects for T-ALL treatment in the near future. In this review, we summarize the epigenetic discoveries made in T-ALL hitherto and discuss possible new venues for epigenetic therapeutic intervention in this aggressive subtype of human leukemia. This article is part of a Directed Issue entitled: Rare Cancers., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Tumor suppressor genes on the X chromosome may skew the gender distribution of specific types of cancer. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with an increased incidence in males. In this study, we report the identification of inactivating mutations and deletions in the X-linked plant homeodomain finger 6 (PHF6) gene in 16% of pediatric and 38% of adult primary T-ALL samples. Notably, PHF6 mutations are almost exclusively found in T-ALL samples from male subjects. Mutational loss of PHF6 is importantly associated with leukemias driven by aberrant expression of the homeobox transcription factor oncogenes TLX1 and TLX3. Overall, these results identify PHF6 as a new X-linked tumor suppressor in T-ALL and point to a strong genetic interaction between PHF6 loss and aberrant expression of TLX transcription factors in the pathogenesis of this disease.

Pinpointing critical regions of recurrent loss may help localize tumor suppressor genes. To determine the regions of loss on chromosome 3p in neuroblastoma, we performed loss of heterozygosity analysis using 16 microsatellite markers in a series of 65 primary tumors and 29 neuroblastoma cell lines. In this study, we report the results and discuss the technical hurdles that we encountered during data generation and interpretation that are of relevance for current studies or tests employing microsatellites. To provide functional support for the implication of 3p tumor suppressor genes in this childhood malignancy, we performed a microcell-mediated chromosome 3 transfer in neuroblastoma cells.

Background: Loss of chromosome 11q defines a subset of high-stage aggressive neuroblastomas. Deletions are typically large and mapping efforts have thus far not lead to a well defined consensus region, which hampers the identification of positional candidate tumour suppressor genes. In a previous study, functional evidence for a neuroblastoma suppressor gene on chromosome 11 was obtained through microcell mediated chromosome transfer, indicated by differentiation of neuroblastoma cells with loss of distal 11q upon introduction of chromosome 11. Interestingly, some of these microcell hybrid clones were shown to harbour deletions in the transferred chromosome 11. We decided to further exploit this model system as a means to identify candidate tumour suppressor or differentiation genes located on chromosome 11., Results: In a first step, we performed high-resolution array CGH DNA copy-number analysis in order to evaluate the chromosome 11 status in the hybrids. Several deletions in both parental and transferred chromosomes in the investigated microcell hybrids were observed. Subsequent correlation of these deletion events with the observed morphological changes lead to the delineation of three putative regions on chromosome 11: 11q25, 11p13-->11p15.1 and 11p15.3, that may harbour the responsible differentiation gene., Conclusion: Using an available model system, we were able to put forward some candidate regions that may be involved in neuroblastoma. Additional studies will be required to clarify the putative role of the genes located in these chromosomal segments in the observed differentiation phenotype specifically or in neuroblastoma pathogenesis in general.

Malignant peripheral nerve sheath tumors (MPNST) are rare soft-tissue malignancies. The genetic basis of these tumors is still poorly understood. Cytogenetic analyses predominantly revealed complex karyotypes, precluding the identification of recurrent chromosomal changes. We report loss of 1p material in a near-diploid karyotype with few or no additional structural chromosome changes in two sporadic cases of MPNST, indicating an important role of 1p loss in MPNST development. In one of these two tumors, a distal 1p deletion (1p31.2 approximately pter) was detected suggesting involvement of a tumor suppressor gene located within this distal region of 1p. Further evidence for recurrent 1p loss in MPNST was obtained by interphase fluorescence in situ hybridization, which showed loss of 1p material in 3 out of 13 tumors. These findings together with data from the literature suggest that loss of a tumor suppressor gene located within distal 1p is implicated in the pathogenesis of MPNST.

We have characterised the DFFB gene, encoding the active subunit of the apoptotic nuclease DNA fragmentation factor (DFF40). DFFB maps to 1p36, near the imprinted putative tumour suppressor gene TP73. The DFFA gene (encoding the inhibitory DFF45 subunit) also maps to 1p36.2-36.3, and we show by FISH that DFFB lies distal to DFFA. We have also mapped a processed DFFB pseudogene to chromosome 9. DFFB itself has seven coding exons spanning 10 kb. Exhaustive mutation screening of 41 neuroblastomas and other tumours in which a 1p36 tumour suppressor gene is implicated showed no tumour-specific mutations. A coding region polymorphism was used to demonstrate uniformly biallelic expression in human fetal DFFB transcripts. Since the putative neuroblastoma tumour suppressor gene in distal 1p36 is predicted to be maternally expressed, the lack of imprinting and absence of somatic mutations in DFFB indicate that it is probably not the neuroblastoma tumour suppressor gene.

Recently, two homologous genes, EXT1 and EXT2, with a putative tumor suppressor function have been described. Mutations in both genes are responsible for multiple exostosis syndrome (EXT), an autosomal dominant condition characterized by the presence of multiple osteochondromas, bony excrescences that sometimes undergo malignant transformation to chondrosarcoma. This family of EXT genes has been extended by the identification of an EXT-like (EXTL) gene showing a high degree of homology with the EXT genes. We report here a second EXT-like gene (EXTL2) which is homologous to the EXT and EXTL genes. EXTL2 consists of 5 exons encoding an ubiquitously expressed protein of 330 amino acids. In addition, a putative pseudogene, EXTL2P was also identified. The EXTL2 gene was assigned to chromosome 1p11-p12, whereas EXTL2P was mapped on chromosome 2q24-q31.

Cytogenetic and molecular studies in neuroblastoma suggest the presence of a tumor suppressor gene at the distal band p36 of human chromosome 1. We described a constitutional translocation t(1;17)(p36;q12-q21), involving the critical region 1p36, in a patient with neuroblastoma, and hypothesized that the translocation predisposed the patient to tumor development. Here we report the molecular delineation of the translocation breakpoints. Somatic cell hybrids were generated by fusion of the patient's fibroblasts with the thymidine kinase deficient hamster cell line, a3. In hybrid cell lines which retained the human derivative chromosomes, the position of chromosome 1p and 17q DNA probes respective to the translocation breakpoints was determined by fluorescence in situ hybridization and Southern blot analysis. The chromosome 1p breakpoint was localized within a repetitive region encoding t-RNA genes, with 12A-2 (PND) as most distal and pHE2.6 (A12M2) as most proximal single-copy breakpoint flanking markers. For the chromosome 17 breakpoint, the proximal and distal flanking markers were identified as 7G4 (NF1) and cMCP-3 (SCYA7), respectively. In this study, cMCP-3 (SCYA7), encoding the human monocyte chemotactic protein-3, was mapped between NF1 and ERBB2. As a pivotal step towards breakpoint cloning, at present these flanking markers optimally delineate the breakpoint regions of both chromosomes 1 and 17 at the molecular level.

Neuroblastoma is characterized by deletions of the short arm of chromosome 1 (1p) and amplification of the N-myc oncogene. We have made somatic cell hybrids of two human neuroblastoma cell lines, one with and one without N-myc expression and amplification. The expression of the amplified N-myc gene is completely switched off in the hybrids. This suggests that N-myc expression results from loss of a repressor function. As N-myc amplification is associated with loss of heterozygosity (LOH) of 1p36, we analysed 1p deletions in 16 neuroblastoma cell lines. The seven cell lines without N-myc amplification have no deletions or relatively small deletions, with an SRO on 1p36.23-33. This suggests that a tumor suppressor gene maps in this region. All nine cell lines with N-myc amplification have larger deletions, with an SRO from 1p35-36.1 to the telomere. This suggests that a second tumor suppressor gene which is associated with N-myc amplification maps more proximally. Fine mapping of 1p36 deletions in the two cell lines of the fusion experiment suggests that the distal locus is not a repressor of N-myc expression, but the more proximal locus could be a candidate for this function.