Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemia

St Jude Children's Research Hospital, Memphis, TN, USA.
Blood (Impact Factor: 10.45). 09/2008; 112(10):4178-83. DOI: 10.1182/blood-2008-06-165027
Source: PubMed


The underlying pathways that lead to relapse in childhood acute lymphoblastic leukemia (ALL) are unknown. To comprehensively characterize the molecular evolution of relapsed childhood B-precursor ALL, we used human 500K single-nucleotide polymorphism arrays to identify somatic copy number alterations (CNAs) in 20 diagnosis/relapse pairs relative to germ line. We identified 758 CNAs, 66.4% of which were less than 1 Mb, and deletions outnumbered amplifications by approximately 2.5:1. Although CNAs persisting from diagnosis to relapse were observed in all 20 cases, 17 patients exhibited differential CNA patterns from diagnosis to relapse. Of the 396 CNAs observed in 20 relapse samples, only 69 (17.4%) were novel (absent in the matched diagnosis samples). EBF1 and IKZF1 deletions were particularly frequent in this relapsed ALL cohort (25.0% and 35.0%, respectively), suggesting their role in disease recurrence. In addition, we noted concordance in global gene expression and DNA copy number changes (P = 2.2 x 10(-16)). Finally, relapse-specific focal deletion of MSH6 and, consequently, reduced gene expression were found in 2 of 20 cases. In an independent cohort of children with ALL, reduced expression of MSH6 was associated with resistance to mercaptopurine and prednisone, thereby providing a plausible mechanism by which this acquired deletion contributes to drug resistance at relapse.

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Available from: Meenakshi Devidas, Mar 14, 2014
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    • "The initial reports suggested the deregulation of Ikaros function occurred at the post-transcriptional level, with increased expression of DN isoform mRNA. However, genomic profiling of additional cohorts of pediatric leukemia identified copy number alterations at the IKZF1 locus [Yang et al. 2008; Kuiper et al. 2007]. These results were confirmed and further refined by Mullighan and colleagues using single nucleotide polymorphism (SNP) arrays on a cohort of Philadelphia chromosome positive B ALL. "
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    ABSTRACT: Ikaros is the founding member of a family of zinc finger transcription factors whose function during early hematopoietic development is required for differentiation into the three major hematopoietic lineages. Ikaros deletions have been described in human malignancies, particularly precursor B-cell leukemia. Deletions of this transcription factor appear to mediate leukemogenesis, although the exact mechanism is unclear. This article reviews the structure and function of Ikaros proteins in chromatin remodeling and gene expression as well as the current knowledge of Ikaros deletions in human malignancies. A new proteomic platform, mass cytometry, is introduced which allows measurements of greater than 30 parameters at the single-cell level and should thus provide a greater level of detail to unravel the mechanistic consequences of Ikaros dysfunction in leukemia.
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    • ". Various groups have shown that genomic arrays can contribute to the discovery and characterization of novel genes involved in the development of ALL [van Vlierberghe et al., 2006; Yang et al., 2008; Sulong et al., 2009; Bardini et al., 2011; Homminga et al., 2011]. For the successful implementation of genomic arrays in the diagnostics of ALL, it is important that the genomic array platform used detects most, if not all, unbalanced abnormalities currently detectable by karyotyping. "
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    ABSTRACT: During the past decade, array CGH has been applied to study copy number alterations in the genome in human leukemia in relation to prediction of prognosis or responsiveness to therapy. In the first segment of this review, we will focus on the identification of acquired mutations by array CGH, followed by studies on the pathogenesis of leukemia associated with germline genetic variants, phenotypic presentation and response to treatment. In the last section, we will discuss constitutional genomic aberrations causally related to myeloid leukemogenesis.
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    • "In the case of PAX5, these abnormalities are generally (a) point mutations located in exons 2, 3, 4, 5, 6, 7, 8, 9, and 10, most of which are clustered within functional domains or (b) alterations in the expression of splice variants of PAX5 [94, 95]. These alterations have been found in up to 32% of children and 30% of adults with B ALL and in 35% of relapsed cases [93, 96, 97]. Almost 35% of patients with PAX5 lesions lack expression of the full-length protein and express only short variants [95]. "
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    ABSTRACT: B cell development starts in bone marrow with the commitment of hematopoietic progenitors to the B cell lineage. In murine models, the IL-7 and preBCR receptors, and the signaling pathways and transcription factors that they regulate, control commitment and maintenance along the B cell pathway. E2A, EBF1, PAX5, and Ikaros are among the most important transcription factors controlling early development and thereby conditioning mice homeostatic B cell lymphopoiesis. Importantly, their gain or loss of function often results in malignant development in humans, supporting conserved roles for these transcription factors. B cell acute lymphoblastic leukemia is the most common cause of pediatric cancer, and it is characterized by unpaired early B cell development resulting from genetic lesions in these critical signaling pathways and transcription factors. Fine mapping of these genetic abnormalities is allowing more specific treatments, more accurately predicting risk profiles for this disease, and improving survival rates.
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