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Recurrent Involvement of Ring-Type Zinc Finger Genes in Complex

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Recurrent Involvement of Ring-Type Zinc Finger Genes in Complex Leukemia (2013) 27, 1745–1791 & 2013 Macmillan Publishers Limited All rights reserved 0887-6924/13 www.nature.com/leu LETTERS TO THE EDITOR Recurrent involvement of ring-type zinc finger genes in complex molecular rearrangements in childhood acute myelogeneous leukemia with translocation t(10;11)(p12;q23) Leukemia (2013) 27, 1745–1791; doi:10.1038/leu.2013.1 the MLL/MLLT10 fusion gene had been detected by conventional FISH and RT-PCR (Table S1). A specimen of the initial and remission sample was obtained in six children; in three of them a Complex rearrangements involving the MLL gene on chromosome relapse sample was available and additionally analyzed after 11q23 and MLLT10 on 10p have been reported in 15% of pediatric informed consent. By analyzing paired-end reads, we were able to patients with MLL rearranged acute myelogeneous leukemia describe these alterations in depth, revealing the precise pattern (AML). Owing to the opposite direction of MLL and MLLT10 of molecular rearrangement and finding other involved chromo- rearrangements (inversion and subsequent translocation or somes. For paired-end sequencing, DNA was isolated from insertion) with three or more breaks are required to result in a peripheral blood lymphocytes, and fragment libraries with a fusion gene.1,2 There are several additional reported median insert size of 450 bp were prepared. Samples of patients recombination partners of the MLL gene, in which a simple 1–3 were sequenced on a GAIIx platform; samples of patients 4–6 reciprocal translocation is insufficient due to incompatible on a HiSeq 2000 (Illumina Inc., San Diego, CA, USA). A orientation.3 However, even more complex rearrangements bioinformatical pipeline for read alignment, removal of duplicate consisting of additional involved chromosomes have been reads and variant detection was applied to find structural described in t(10;11).4 Chromosomal translocations t(10;11) alterations based on mapping coordinates, insert size and (p12;q14–23) always lead to fusion of the 50end of MLL and orientation of reads. By sequencing the remission sample we 30end of MLLT10. The MLLT10 fusion partner codes for two excluded inherited sequence variants. Copy number variations adjacent alpha helical domains and a leucine zipper motif were detected by coverage normalization, and computation of embedded within a region of 82 amino acids, proposed to be copy number ratios between diseased and remission sample. indispensable for induction of leukemia.5,6 The gold standard to Conventional PCR and capillary sequencing validated selected detect suspected translocations in AML patients are fluorescence translocations detected by paired-end read analysis. For further in situ hybridization (FISH) studies and subsequent reverse methodical details we refer to our supplemental file. transcriptase-polymerase chain reaction (RT-PCR). However, next Our pipeline was able to reveal the defining MLL/MLLT10 generation sequencing has emerged as a powerful tool to translocation with its precise genomic coordinates in each understand complex genetic traits. Here, we applied low- leukemic sample (except relapse in patient 4). Consistent with coverage whole-genome sequencing on six pediatric patients past publications we observed heterogeneity in breakpoints with t(10;11) AML (FAB-M4/M5), in which MLL rearrangement and within the breakpoint cluster regions of MLL and MLLT10, Table 1. Upper rows: breakpoint (bp) heterogeneity and features in MLL/MLLT10 translocations Patient 1 2 3 4 5 6 Bp in MLLT10 p12.31, intron p12.31, intron 5–6 p12.31, p12.31, intron p12.31, p12.31, intron 9–10 8–9 intron 5–6 intron 9–10 8–9 Bp in MLL q23.3, intron q23.3, intron 8–9 q23.3, q23.3, intron q23.3, intron q23.3, intron 8–9 10–11 intron 8–9 8–9 8–9 Second break q14.1, no gene q23.3, no gene q12.1, q23.3 RNF214, q14.3, no q13.4 RNF169, Chromosome 11 no gene intron 5–6 gene intron 2–3 Features Inversion and Inversion and translocation, CNV Insertion Insertion, Inversion Inversion and partial translocation, ( þ ) chromosome 1,13,21 ( À ) chromosome and insertion, CNV chromosome chromosome: 2 22 involved translocation ( þ )chromosome 8 16 involved IR I I I RIR I Translocations 24 21 36 412 6 1 11 17 5 Deletions 3827 3108 1193 49 21 25 27 14 1 Inversions 15 13 14 16 0 0 11 12 3 Abbreviations: CNV, copy number variation; I, initial; R, relapse. In all patients, paired-end sequencing revealed the pattern of molecular rearrangement. ( þ ) indicates gains, ( À ) losses. Lower rows: number of detected structural variants. Patients 1–3 were sequenced on the GAIIx with a significant lower coverage, thus variants with at least two supporting reads have been counted; in patients 4–6 (HiSeq2000) variants had at least three supporting reads. Accepted article preview online 9 January 2013; advance online publication, 15 February 2013 Letters to the Editor 1746 Figure 1. Patient 4 (upper panel) and patient 6 (lower panel) (a) FISH analysis: green color of the MLL probe identifies the proximal 50 part of the MLL gene, red color identifies the distal 30part of the gene. The MLL probe shows a MLL split signal on different chromosomes, on 10p and 11q, respectively, indicating an insertion in patient 4 and 6. (b) Karyotyping results. (c) Rearrangement profile: molecular pattern of rearrangement, revealed by paired-end sequencing. The illustration consists of a normal reference genome in the upper region with found paired-end reads (for example, m1 and m1a) aligned to the genome. As each read (for example, m1) is supposed to be orientated to its mate (for example, m1a), the type of rearrangement can be deduced; for example, upper panel: m4a and m4 orientated towards each other suggest a deletion, m1 and m1a on different chromosomes suggest a translocation; lower panel: m2 and m2a are located on the same strand and are orientated in the same direction, indicating an inversion. (d) Upper panel: schematic overview of the complex translocations between chromosome 10, 11 and 22, harboring the MLL/MLLT10 fusion gene. Furthermore, the fusion gene RNF214/MLL is depicted. The fusion sequence MLL/MLLT10 and t(22;11) was further validated by capillary sequencing, revealing the breakpoint at one-bp level. Lower panel: schematic overview of the translocation harboring the MLL/MLLT10 fusion gene and MLLT10/RNF169 fusion gene. The latter fusion sequence was further validated by capillary sequencing, revealing the breakpoint at 1-bp level. (e) CIRCOS plot of the initial sample: genomic landscape of interchromosomal translocations were scattered across the whole genome and allocated along the outer ring (chromosome ideograms). The inner ring represents copy number status in terms of gains and losses. However, only variants supported by 42 reads (in patient 1–3) and 43 reads (in patient 4–6) were transferred into this plot (f) CNV plot: deep blue-colored bars indicate the copy number determined by sequencing data in relation to the reference genome. In case of gains and losses bars are elevated or lowered. Leukemia (2013) 1745 – 1791 & 2013 Macmillan Publishers Limited Letters to the Editor 1747 respectively. Furthermore, we detected numerous structural reads, we could exactly deduce the molecular anatomy of the variants in leukemic samples not found in the remission material rearrangement. In patients 3, 4 and 6, we found an inversion (Table 1). Briefly, we see classical t(10;11) rearrangements in followed by an insertion, in patient 1, 2 and 5 an inversion patients 3 and 5, which were also found by cytogenetics and FISH. followed by a translocation. Van Limbergen7 classified these In patient 3 (Figure S4), reads were found, suggestive of a missing reported molecular rearrangements as type I (patients 3, 4 and 6) region on chromosome 11 containing part of the MLL gene. and type II (patients 1, 2 and 5). In most patients we determined Further reads suggested that this MLL gene fragment was the breakpoints down to the nucleotide level by validating the subsequently inserted into the MLLT10 gene. In patient 5 breakpoint by PCR. We identified additional chromosomal fusions (Figure S5), reads indicated an inversion of a region of that were not being detected by routine cytogenetics; in patient 6 chromosome 11 that encodes partially for the MLL gene. we found a new subtype of rearrangement, which has not been Subsequently the inverted fragment and the q-terminal part was described before. Though FISH probes and cytogenetic banding translocated into the MLLT10 gene. Validation PCR and capillary techniques clearly identify the t(10;11) MLLT10/MLL translocation, sequencing verified the MLL/MLLT10 breakpoint in both patients. paired-end sequencing allowed to identify additional structural In patient 1 and 4, in contrast to FISH and cytogenetics, paired-end variants. It is certainly of great interest to know how many of the analysis revealed the involvement of additional chromosomal other previously reported t(10;11) harbor this type of rearrange- material inserted at the t(10;11) breakpoint. In patient 1 (Figure ment. In two patients we observed the reciprocal fusion of ring S1), we saw an additional breakpoint on 16q23.3. In patient 4 finger protein genes to the 30 MLL gene. RNF214 consists of a (Figure 1, upper panel), reads indicated the involvement of three conserved cysteine-rich domain that is able to bind zinc atoms. chromosomes (10, 11 and 22). We found read pairs on 11q23.3 Proteins with this domain are mostly involved in the ubiquiti- (m4, m4a) orientated towards each other but encompassing a 1- nation pathway of protein degradation. In recent publications, Mb-spanning region, suggestive of a ‘deletion’. Furthermore, at RNF169 was identified as a paralog to RNF168.8,9 RNF8/RNF168 both ends of this region we found reads, which had their origin in signaling is involved in the repair pathway of double stranded the intronic region 5–6 of the MLLT10 gene (p12.31), leading to the breaks; RNF169 is supposed to regulate this signaling pathway in MLL/MLLT10 fusion gene (m1, m1a), and at 22q12.3 (m3, m3a), magnitude.9 However, the precise function of RNF214 and RNF168, respectively.
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