Trisomies in Hematologic Malignancies

Acquired clonal chromosome aberrations, closely associated with leukemogenesis, are found in many hematologic malignancies. Although the balanced rearrangements, such as translocations and inversions, are the ones most commonly thought of in the context of leukemias, gains of chromosomes ? e.g.., trisomies ? are also frequent. Little is known about the biologic outcome, the pathogenetic significance, or the mechanism behind the formation of the latter genetic changes. The aim of the present thesis was to address these issues, focusing on trisomy 8 as the sole cytogenetic change in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), and on high hyperdiploidy ? gains of multiple chromosomes ? in childhood acute lymphoblastic leukemia (ALL). In the first two articles, AML and MDS cases with +8 as the seemingly sole abnormality were studied with fluorescence in situ hybridization (FISH) analysis and high-resolution genome-wide array-based comparative genome hybridization (array CGH), respectively, in order to determine whether this chromosome abnormality was truly isolated or if there were additional, cytogenetically cryptic, anomalies present. Whereas multicolor-FISH, FISH with partial chromosome paint and subtelomeric probes for 8p and 8q, and FISH with probes specific for four leukemia-associated chromosome 8 genes failed to reveal any hidden genetic changes, array CGH identified twelve previously undetected imbalances, involving 0.2 ? 4.9 Mb and many genes, of putative importance in the leukemogenesis. Thus, it was shown that trisomy 8 is not always the primary genetic event, even when it is the sole anomaly seen with standard cytogenetic methods. In articles III and IV, the formation of hyperdiploidy and the possibility of imprinting effects related to the parental origin of the chromosomes gained in this cytogenetic subgroup were investigated. Combining the results from the two studies, it could, for the first time, be demonstrated that hyperdiploidy most frequently arises by a simultaneous gain of chromosomes in a single abnormal cell division, with a subset of cases occurring by other pathways. Furthermore, preferential duplication of maternal or paternal homologues was not seen for any of the commonly gained chromosomes in these investigations. Hence, imprinting effects resulting from such skewness could be excluded as the pathogenetically important outcome of the extra chromosomes in hyperdiploid childhood ALL. In summary, the results presented in this thesis have extended our knowledge of trisomies in malignant hematologic disorders and increased the understanding of their significance in the leukemogenic processes

Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011.

Despite the favorable prognosis of childhood acute lymphoblastic leukemia (ALL), a substantial subset of patients relapses. Since this occurs not only in the high risk but also in the standard/intermediate groups, the presently used risk stratification is suboptimal. The underlying mechanisms for treatment failure include presence of genetic changes causing insensitivity to the therapy administered. To identify relapse-associated aberrations we performed single nucleotide polymorphism array analyses of 307 uniformly treated, consecutive pediatric ALL cases accrued 1992-2011. Recurrent aberrations of 14 genes in patients who subsequently relapsed or had induction failure were detected. Of these, deletions/uniparental isodisomies of ADD3, ATP10A, EBF1, IKZF1, PAN3, RAG1, SPRED1, and TBL1XR1 were significantly more common in B-cell precursor ALL patients who relapsed compared with those remaining in complete remission. In univariate analyses, age (10 years), WBC counts (>100 × 109/l), t(9;22)(q34;q11), MLL rearrangements, near-haploidy, and deletions of ATP10A, IKZF1, SPRED1, and the pseudoautosomal 1 regions on Xp/Yp were significantly associated with decreased 10-year event-free survival, with IKZF1 abnormalities being an independent risk factor in multivariate analysis irrespective of risk group. High age and deletions of IKZF1 and SPRED1 were also associated with poor overall survival. Thus, analyses of these genes provide clinically important information.Leukemia accepted article preview online, 4 July 2013; doi:10.1038/leu.2013.206

Omfördelning av Gränby Sportfälts effektuttag

There is currently a power shortage in the electric grid around Uppsala, which obstructs the local development, since it prevents companies from expanding their businesses. Sportfastigheter is a part of Uppsala municipality and operates the ice halls at Gränby Sportfält, which occasionally require large power outputs. The purpose of this study is, therefore, to examine whether flow batteries could be a possible technique to redistribute the power output from the electric grid. Type, size and steering of a flow battery have been examined through simulations. Flow batteries have also been compared to other energy storage methods and the implementation of a possible capacitor bank has been investigated. The result is, that flow batteries is a possible technique to cut power tops at Gränby sportfält, while other storage methods should be investigated more closely, since flow batteries is a rather new and unproven technique. If the installation would be made today, a more established storage method such as lithium ion batteries would be preferable, even though flow batteries have a promising future potential. The installation of a capacitor bank can be considered since it would compensate the reactive effect and, hence, reduce the power output at Gränby Sportfält.Det råder idag kapacitetsbrist i Uppsalas elnät vilket bromsar den lokala utvecklingen eftersom det hindrar företag från att bygga ut sina verksamheter. Sportfastigheter är en del av Uppsala kommun och förvaltar ishallarna vid Gränby Sportfält, som stundtals kräver mycket stora effektuttag. Syftet med denna studie är att undersöka om flödesbatterier kan vara en möjlig teknik för att omfördela effektuttaget från elnätet. Typ, storlek och styrning av ett flödesbatteri har undersökts genom simuleringar. Flödesbatterier har även jämförts med andra energilagringsmetoder och implementeringen av en eventuell kondensatorbank har undersökts. Resultatet är att flödesbatterier är en möjlig teknik för att kapa effekttopparna för Gränby Sportfält men att andra lagringsmetoder bör undersökas närmare, eftersom flödesbatterier är en relativt ny och obeprövad metod. Om installation skulle göras i dagsläget vore en mer etablerad lagringsmetod såsom litiumjonbatterier att föredra, även om flödesbatterier har en lovande framtidspotential. Installationen av en kondensatorbank kan övervägas då det skulle kompensera för den reaktiva effekten och på sätt minska effektuttaget för Gränby Sportfält

The genomic landscape of high hyperdiploid childhood acute lymphoblastic leukemia.

High hyperdiploid (51-67 chromosomes) acute lymphoblastic leukemia (ALL) is one of the most common childhood malignancies, comprising 30% of all pediatric B cell-precursor ALL. Its characteristic genetic feature is the nonrandom gain of chromosomes X, 4, 6, 10, 14, 17, 18 and 21, with individual trisomies or tetrasomies being seen in over 75% of cases, but the pathogenesis remains poorly understood. We performed whole-genome sequencing (WGS) (n = 16) and/or whole-exome sequencing (WES) (n = 39) of diagnostic and remission samples from 51 cases of high hyperdiploid ALL to further define the genomic landscape of this malignancy. The majority of cases showed involvement of the RTK-RAS pathway and of histone modifiers. No recurrent fusion gene-forming rearrangement was found, and an analysis of mutations on trisomic chromosomes indicated that the chromosomal gains were early events, strengthening the notion that the high hyperdiploid pattern is the main driver event in this common pediatric malignancy

High modal number and triple trisomies are highly correlated favorable factors in childhood B-cell precursor high hyperdiploid acute lymphoblastic leukemia treated according to the NOPHO ALL 1992/2000 protocols.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Between 1992 and 2008, 713 high hyperdiploid acute lymphoblastic leukemias in children aged 1-15 years were diagnosed and treated according to the Nordic Society for Pediatric Hematology and Oncology acute lymphoblastic leukemia 1992/2000 protocols. Twenty (2.8%) harbored t(1;19), t(9;22), der(11q23), or t(12;21). The median age of patients with "classic" high hyperdiploidy was lower than that of patients with translocation-positive high hyperdiploidy (P53/55 (P=0.020/0.024). In multivariate analyses, modal number and triple trisomies were significantly associated with superior event-free survival in separate analyses with age and white blood cell counts. When including both modal numbers and triple trisomies, only low white blood cell counts were significantly associated with superior event-free survival (P=0.009). We conclude that high modal chromosome numbers and triple trisomies are highly correlated prognostic factors and that these two parameters identify the same subgroup of patients characterized by a particularly favorable outcome.Swedish Childhood Cancer Foundation Swedish Cancer Society Swedish Research Counci

Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia.

Hyperdiploidy, i.e. gain of whole chromosomes, is one of the most common genetic features of childhood acute lymphoblastic leukemia (ALL), but its pathogenetic impact is poorly understood. Here, we report a proteogenomic analysis on matched datasets from genomic profiling, RNA-sequencing, and mass spectrometry-based analysis of >8,000 genes and proteins as well as Hi-C of primary patient samples from hyperdiploid and ETV6/RUNX1-positive pediatric ALL. We show that CTCF and cohesin, which are master regulators of chromatin architecture, display low expression in hyperdiploid ALL. In line with this, a general genome-wide dysregulation of gene expression in relation to topologically associating domain (TAD) borders were seen in the hyperdiploid group. Furthermore, Hi-C of a limited number of hyperdiploid childhood ALL cases revealed that 2/4 cases displayed a clear loss of TAD boundary strength and 3/4 showed reduced insulation at TAD borders, with putative leukemogenic effects

Clonal Evolution through Loss of Chromosomes and Subsequent Polyploidization in Chondrosarcoma

Near-haploid chromosome numbers have been found in less than 1% of cytogenetically reported tumors, but seem to be more common in certain neoplasms including the malignant cartilage-producing tumor chondrosarcoma. By a literature survey of published karyotypes from chondrosarcomas we could confirm that loss of chromosomes resulting in hyperhaploid-hypodiploid cells is common and that these cells may polyploidize. Sixteen chondrosarcomas were investigated by single nucleotide polymorphism (SNP) array and the majority displayed SNP patterns indicative of a hyperhaploid-hypodiploid origin, with or without subsequent polyploidization. Except for chromosomes 5, 7, 19, 20 and 21, autosomal loss of heterozygosity was commonly found, resulting from chromosome loss and subsequent duplication of monosomic chromosomes giving rise to uniparental disomy. Additional gains, losses and rearrangements of genetic material, and even repeated rounds of polyploidization, may affect chondrosarcoma cells resulting in highly complex karyotypes. Loss of chromosomes and subsequent polyploidization was not restricted to a particular chondrosarcoma subtype and, although commonly found in chondrosarcoma, binucleated cells did not seem to be involved in these events

Drug-resilient cancer cell phenotype is acquired via polyploidization associated with early stress response coupled to HIF-2α transcriptional regulation

Therapeutic resistance and recurrence remain core challenges in cancer therapy. How therapy resistance arises is currently not fully understood with tumors surviving via multiple alternative routes. Here, we demonstrate that a subset of cancer cells survives therapeutic stress by entering a transient state characterized by whole genome doubling. At the onset of the polyploidization program, we identified an upregulation of key transcriptional regulators, including the early stress-response protein AP-1 and normoxic stabilization of HIF-2α. We found altered chromatin accessibility, ablated expression of RB1, and enrichment of AP-1 motif accessibility. We demonstrate that AP-1 and HIF-2α regulate a therapy resilient and survivor phenotype in cancer cells. Consistent with this, genetic or pharmacologic targeting of AP-1 and HIF-2α reduced the number of surviving cells following chemotherapy treatment. The role of AP-1 and HIF-2α in stress-response by polyploidy suggest a novel avenue for tackling chemotherapy-induced resistance in cancer