The MLL partial duplication in acute myeloid leukemia

Division of Haematology and Oncology, University of Goettingen, Goettingen, Germany.
British Journal of Haematology (Impact Factor: 4.71). 12/2006; 135(4):438-49. DOI: 10.1111/j.1365-2141.2006.06301.x
Source: PubMed


Mixed lineage leukaemia gene-partial tandem duplications (MLL-PTD) characterise acute myeloid leukaemia (AML) with trisomy 11 and AML with a normal karyotype. MLL-PTD confer a worse prognosis with shortened overall and event free survival in childhood and adult AML. In spite of these clinical observations, the leukaemogenic mechanism has, so far, not been determined. This review summarises clinical studies on MLL-PTD positive AML and recent experimental findings on the putative leukaemogenic role of MLL-PTD.

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    • "A tandem duplication can be further classified as either a partial tandem duplication (PTD, e.g. [3]), if both edges of the duplicated segment correspond to annotated exon boundaries that are involved in splicing (Figure  1B); or an internal tandem duplication (ITD, e.g. [4]) otherwise (Figure  1C). "
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    ABSTRACT: Chimeric transcripts, including partial and internal tandem duplications (PTDs, ITDs) and gene fusions, are important in the detection, prognosis, and treatment of human cancers. We describe Barnacle, a production-grade analysis tool that detects such chimeras in de novo assemblies of RNA-seq data, and supports prioritizing them for review and validation by reporting the relative coverage of co-occurring chimeric and wild-type transcripts. We demonstrate applications in large-scale disease studies, by identifying PTDs in MLL, ITDs in FLT3, and reciprocal fusions between PML and RARA, in two deeply sequenced acute myeloid leukemia (AML) RNA-seq datasets. Our analyses of real and simulated data sets show that, with appropriate filter settings, Barnacle makes highly specific predictions for three types of chimeric transcripts that are important in a range of cancers: PTDs, ITDs, and fusions. High specificity makes manual review and validation efficient, which is necessary in large-scale disease studies. Characterizing an extended range of chimera types will help generate insights into progression, treatment, and outcomes for complex diseases.
    BMC Genomics 08/2013; 14(1):550. DOI:10.1186/1471-2164-14-550 · 3.99 Impact Factor
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    • "Growing evidence suggests that increased HOXa gene expression associated with MLL1 amplifications and MLL1-PTDs underlie the pathogenesis of these leukemias (Basecke et al., 2006; Dorrance et al., 2006). HOXa gene expression is dependent on the histone methyltransferase activity of MLL1 ((Milne et al., 2002), and given the increased H3K4 methylation observed in MLL1-PTDs (Dorrance et al., 2008; Dorrance et al., 2006), inhibitors that down-regulate the histone methyltransferase activity of MLL1-PTD have the potential to reverse this aberrant epigenetic program. "

    Acute Leukemia - The Scientist's Perspective and Challenge, 12/2011; , ISBN: 978-953-307-553-2
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    • "Approximately 4-11% of patients with AML present with rearrangement of the MLL (also known as ALL1 or HRX) gene as the result of a PTD within a single MLL allele [81]. This aberration tends to be frequent in AML patients without chromosomal abnormalities [81]. "
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    ABSTRACT: The development of acute myeloid leukemia (AML) is a multistep process that requires at least two genetic abnormalities for the development of the disease. The identification of genetic mutations in AML has greatly advanced our understanding of leukemogenesis. Recently, the use of novel technologies, such as massively parallel DNA sequencing or high-resolution single-nucleotide polymorphism arrays, has allowed the identification of several novel recurrent gene mutations in AML. The aim of this review is to summarize the current findings for the identification of these gene mutations (Dnmt, TET2, IDH1/2, NPM1, ASXL1, etc.), most of which are frequently found in cytogenetically normal AML. The cooperative interactions of these molecular aberrations and their interactions with class I/II mutations are presented. The prognostic and predictive significances of these aberrations are also reviewed.
    Journal of Hematology & Oncology 09/2011; 4(1):36. DOI:10.1186/1756-8722-4-36 · 4.81 Impact Factor
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