Kawamata N, Ogawa S, Zimmermann M, Kato M, Sanada M, Hemminki K et al.. Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution single nucleotide polymorphism oligonucleotide genomic microarray. Blood 111: 776-784

Department of Hematology, Oncology, Cedars-Sinai Medical Center/University of California at Los Angeles School of Medicine 90048, USA.
Blood (Impact Factor: 10.45). 02/2008; 111(2):776-84. DOI: 10.1182/blood-2007-05-088310
Source: PubMed


Pediatric acute lymphoblastic leukemia (ALL) is a malignant disease resulting from accumulation of genetic alterations. A robust technology, single nucleotide polymorphism oligonucleotide genomic microarray (SNP-chip) in concert with bioinformatics offers the opportunity to discover the genetic lesions associated with ALL. We examined 399 pediatric ALL samples and their matched remission marrows at 50,000/250,000 SNP sites using an SNP-chip platform. Correlations between genetic abnormalities and clinical features were examined. Three common genetic alterations were found: deletion of ETV6, deletion of p16INK4A, and hyperdiploidy, as well as a number of novel recurrent genetic alterations. Uniparental disomy (UPD) was a frequent event, especially affecting chromosome 9. A cohort of children with hyperdiploid ALL without gain of chromosomes 17 and 18 had a poor prognosis. Molecular allelokaryotyping is a robust tool to define small genetic abnormalities including UPD, which is usually overlooked by standard methods. This technique was able to detect subgroups with a poor prognosis based on their genetic status.

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Available from: Yasuhito Nannya
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    • "However, there are clear immunophenotypic differences between DS-ALL and non-DS-ALL, with mature B-cell ALL (Burkitt leukemia) and T-cell ALL being exceedingly rare in patients with DS; virtually all DS-ALL cases display a B-cell precursor (BCP) phenotype [11,13,19-21]. As regards acquired genetic differences, although single nucleotide polymorphism (SNP) analyses have in general identified similar microdeletions in DS-ALL and non-DS-ALL cases [16,22-25], DS-ALL and non-DS-ALL are to a large extent cytogenetically distinct – DS-ALL are rarely high hyperdiploid (51–67 chromosomes) and seldom display MLL rearrangements or t(9;22)(q34;q11)/BCR-ABL1[5,20,26,27]. The lack of specific ALL-associated gene fusions precludes risk group assignment and hence treatment stratification based on cytogenetics in most instances of DS-ALL. "
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    ABSTRACT: Children with Down syndrome (DS) have an increased risk for acute lymphoblastic leukemia (ALL). Although previous studies have shown that DS-ALL differs clinically and genetically from non-DS-ALL, much remains to be elucidated as regards genetic and prognostic factors in DS-ALL. To address clinical and genetic differences between DS-ALL and non-DS-ALL and to identify prognostic factors in DS-ALL, we ascertained and reviewed all 128 pediatric DS-ALL diagnosed in the Nordic countries between 1981 and 2010. Their clinical and genetic features were compared with those of the 4,647 B-cell precursor (BCP) ALL cases diagnosed during the same time period. All 128 DS-ALL were BCP ALL, comprising 2.7% of all such cases. The 5-year event-free survival (EFS) and overall survival (OS) were significantly (P = 0.026 and P = 0.003, respectively) worse for DS-ALL patients with white blood cell counts >=50 x 109/l. The age distributions varied between the DS and non-DS cases, with age peaks at 2 and 3 years, respectively; none of the DS patients had infant ALL (P = 0.029). The platelet counts were lower in the DS-ALL group (P = 0.005). Abnormal karyotypes were more common in non-DS-ALL (P < 0.0001), and there was a significant difference in the modal number distribution, with only 2% high hyperdiploid DS-ALL cases (P < 0.0001). The 5-year EFS and 5-year OS were significantly worse for DS-ALL (0.574 and 0.691, respectively) compared with non-DS-ALL (0.783 and 0.894, respectively) in the NOPHO ALL-1992/2000 protocols (P < 0.001). The present study adds further support for genetic and clinical differences between DS-ALL and non-DS-ALL.
    Full-text · Article · Apr 2014 · Journal of Hematology & Oncology
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    • "y Kawamata et al., 2008; Mullighan et al., 2008; Parker et al., 2008; Lilljebjorn et al., 2010 "
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    ABSTRACT: ETV6-RUNX1 fusion [t(12;21)(p13;q22)] occurs in 25% of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and is associated with a favorable outcome. Additional abnormalities involving der(21)t(12;21) and nonrearranged chromosome 12 are well characterized but aberrations involving the der(12)t(12;21) have rarely been described. Herein, we describe two novel abnormalities affecting the der(12)t(12;21): a deletion (20/247, 8%) and duplication (10/247, 4%). All 30 patients were under 10 years of age, had a median white blood count of 12.4 × 10(9) /L and 19.2 × 10(9) /L, respectively, with a good outcome. Deletions of der(12)t(12;21) on both sides of the breakpoint were confirmed and mapped: centromeric (12p11.21-12p13.2) and telomeric (21q22.12-21q22.3). The size of these deletions extended from 0.4-13.4 to 0.8-2.5 Mb, respectively. The centromeric deletion encompassed the following genes: LRP6, BCL2L14, DUSP16, CREBL2, and CDKN1B. We postulate that this deletion occurs at the same time as the translocation because it was present in all ETV6-RUNX1-positive cells. A second abnormality representing duplication of the reciprocal RUNX1-ETV6 fusion gene was a secondary event, which we hypothesize arose through mitotic recombination errors. This led to the formation of the following chromosome: der(12)(21qter→21q22.12::12p13.2-12p12.3::12p12.3→12qter). Both abnormalities affect the reciprocal RUNX1-ETV6 fusion product which could either eliminate or amplify its expression and thus contribute to leukemogenesis. However, other consequences such as haploinsufficiency of tumor suppressor genes and amplification of oncogenes could also be driving forces behind these aberrations. In conclusion, this study has defined novel abnormalities in ETV6-RUNX1 BCP-ALL, which implicate new genes involved in leukemogenesis. © 2012 Wiley Periodicals, Inc.
    Full-text · Article · Feb 2013 · Genes Chromosomes and Cancer
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    • "In addition, approximately one quarter of B-ALL cases, defined as “B-NEG” throughout the text, lack recurring cytogenetic and molecular abnormalities, and the genetic basis of these cases is unknown [1], [3], [4]. Recently, genome-wide approaches to study DNA copy number abnormalities and loss of heterozygosity (LOH) events led to impressive progresses and revolutionized the knowledge of the genetic basis of ALL [5], [6], [7], [8]. In B-ALL a high frequency of genetic abnormalities in key pathways, including lymphoid differentiation, cell cycle regulation, tumor suppression, and drug responsiveness, have been identified [9], [10]. "
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    ABSTRACT: Deletions of IKAROS (IKZF1) frequently occur in B-cell precursor acute lymphoblastic leukemia (B-ALL) but the mechanisms by which they influence pathogenesis are unclear. To address this issue, a cohort of 144 adult B-ALL patients (106 BCR-ABL1-positive and 38 B-ALL negative for known molecular rearrangements) was screened for IKZF1 deletions by single nucleotide polymorphism (SNP) arrays; a sub-cohort of these patients (44%) was then analyzed for gene expression profiling. Total or partial deletions of IKZF1 were more frequent in BCR-ABL1-positive than in BCR-ABL1-negative B-ALL cases (75% vs 58%, respectively, p = 0.04). Comparison of the gene expression signatures of patients carrying IKZF1 deletion vs those without showed a unique signature featured by down-regulation of B-cell lineage and DNA repair genes and up-regulation of genes involved in cell cycle, JAK-STAT signalling and stem cell self-renewal. Through chromatin immunoprecipitation and luciferase reporter assays we corroborated these findings both in vivo and in vitro, showing that Ikaros deleted isoforms lacked the ability to directly regulate a large group of the genes in the signature, such as IGLL1, BLK, EBF1, MSH2, BUB3, ETV6, YES1, CDKN1A (p21), CDKN2C (p18) and MCL1. Here we identified and validated for the first time molecular pathways specifically controlled by IKZF1, shedding light into IKZF1 role in B-ALL pathogenesis.
    Full-text · Article · Jul 2012 · PLoS ONE
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