MLLT10 (previously called AF10) is a moderately common MLL fusion partner predominantly occurring in acute monoblastic leukemia (AML-M5). 10;11 rearrangements require at least three breaks in order to generate an in-frame MLL-MLLT10 fusion as a result of the opposite orientations of both genes on the respective chromosome arms. In this study, we describe a detailed molecular cytogenetic analysis of MLL-MLLT10 positive 10;11 rearrangements in two patients. We observed an as yet unreported chromosomal mechanism with at least four breakpoints, leading to MLL-MLLT10 gene fusion in a 24-year-old male. An inversion of 11q13-q23 with a breakpoint in the MLL gene was followed by an additional break 3′ of MLL prior to insertion of the 11q segment into MLLT10. In a second patient, a 37-year-old male with AML-M5b, molecular cytogenetic analysis of an apparent 10;11 reciprocal translocation showed an intrachromosomal inversion of 3′MLLT10followed by a reciprocal translocation between 10p12 and 11q23. Review of the literature showed that all cases were the result of an inversion of either 10p or 11q followed by translocation 10p;11q or insertion of the inverted segment into MLLT10 or MLL.
MLL rearrangements occur in approximately 5–10% of acute lymphoid and myeloid leukemias, poorly differentiated or biphenotypic leukemias and myelodysplastic syndromes, and are typically associated with a poor prognosis, both in children and adults. The MLL gene is highly promiscuous with more than 20 partner genes now identified.1,2,3 MLL rearrangements may be readily detectable by cytogenetic analysis, eg in the case of the t(4;11)(q21;q23), but can be easily overlooked when partner genes are located at distal ends of chromosomes, eg in the t(9;11)(p22;q23) and t(11;19)(q23;p13).4,5,6 The majority of MLL abnormalities are the result of reciprocal translocations. An exception is the MLL rearrangement with MLLT10,7 a moderately common partner gene, which is found in different types of chromosomal 10;11 rearrangements.8,9,10,11 Non-random chromosomal rearrangements involving chromosomes 10 and 11 were identified by cytogenetic analysis, but with the type of rearrangements and breakpoints being variable. A significant proportion of these 10;11 abnormalities was shown to result in MLL-MLLT10 fusion,8,9,10,11,12,13,14,15,16,17 although the occurrence of two other possible transcripts, CALM-MLLT10 and MLL-ABI1 has been described.10,18,19,20 The nature and complexity of these 10;11 rearrangements was first described by Beverloo et al8 and explained by the opposite orientation of both genes on the respective chromosome arms. In this study, we performed a detailed molecular cytogenetic analysis of 10;11 rearrangements in two patients. We describe a new chromosomal mechanism leading to MLL-MLLT10 fusion and observed alternative splicing of an as yet unreported MLL-exon-8-MLLT10 fusion, resulting in three different isoforms.
Furthermore, we present an overview of the different chromosomal mechanisms leading to MLL-MLLT10-positive 10;11 rearrangements described in 16 leukemia patients which were investigated with FISH.
Patient 1 was a 24-year-old Caucasian male who presented with persistent fatigue, weight loss and night sweating. Blood analysis revealed pancytopenia. The bone marrow was hypercellular with 98% blast cells. These cells with plentiful cytoplasm were strongly basophilic, and one or more large prominent nucleoli and fine chromatin structure were present. Cytochemical staining showed a strong naphtol AS-D acetate esterase (NASDA) activity, inhibited by NaF. This is characteristic for monocytic leukemia. Immunophenotyping of the blast cells was positive for CD33, HLA-DR and CD11C, which provides further evidence for the nature of the malignant cells.
Induction chemotherapy type IVA I with Ara-C, idarubicin and VP16 was started. After a second round of chemotherapy with amsacrine and Ara-C, the patient reached complete remission. He received two additional rounds of chemotherapy and complete remission was sustained. Bone marrow transplantation was suggested, but no HLA-identical donor could be found. The patient is still doing well 50 months after diagnosis.
A 37-year-old male was originally presented at the hospital with loss of weight and swollen lymph nodes. Bone marrow biopsy revealed a hypercellular marrow largely replaced by an extensive population of monocytic precursors (monoblasts and promonocytes) and abnormal monocytes. Cytochemical analysis was positive for Sudan black B (SBB) and α-naphtylacetate esterase (ANAE), which was inhibited by NaF. Immunophenotyping of the blast cells was CD45, CD33, CD34, CD15, CD13, HLA-DR, CD11c and CD11b positive. Thus the bone marrow aspirate was consistent with AML-M5b.
The patient was treated according to the EORTC-protocol 06991 and achieved a complete remission. Following induction and consolidation therapy, progression of the disease was observed. Therefore, the patient entered a second treatment with idarubicin and fludarabine and attained complete remission. He then underwent an allogenic bone marrow transplantation from a HLA-compatible donor. Four months post-transplantation the patient is doing well.
Materials and methods
Bone marrow and peripheral blood cells were cultured and harvested according to standard procedures. Karyotypic analysis was performed on G-banded metaphases. The karyotype was described according to the recommendations of ISCN.23
Fluorescence in situ hybridization (FISH)
Probe labelling and FISH was performed as described according to standard procedures.24 Biotin and digoxigenin-modified probes were visualized using avidin-FITC and sheep-anti-digoxigenin-TRITC or using avidin-Cy5 and sheep-anti-digoxigenin-TexasRed.25 The MLL spanning dual color probe (Vysis, Downers Grove, IL, USA) is a commercially available directly labelled probe (SpectrumOrange and SpectrumGreen). For multiple-color FISH, a combination of four different fluorochromes was used. Sequential images for each fluorochrome and the DAPI counterstain were captured on a Zeiss Axioplan microscope using the appropriate single-bandpass filters. The M-FISH ISIS software program from MetaSystems (Altlussheim, Germany) for image capture and false color modification was used for simultaneous visualization of each fluorochrome and for assignment of false colors for each of the fluorochromes. The following probes were used: chromosome plasmid libraries pBS-10 and pBS-11,26 YAC 807_b_3 containing MLLT10,18 RP11–418C1 located telomeric to MLLT10 and also containing the 5′ part of the gene, RP11-177H22 located within the MLLT10 gene, RP11-249M6 and RP11-399C16 almost completely overlapping and located centromeric to MLLT10 and also containing the 3′ part of the gene, RP11-251H5 (10p11.21), subtelomeric 10p YAC TYAC95 (a kind gift from Dr A Jauch, Institute of Human Genetics, Heidelberg, Germany),27 YACs 742_f_9 and 856_b_9 spanning the MLL gene and ∼1.0 Mb of sequences located distal to MLL,8,19 MLL spanning probes (Vysis), YACs 946_f_4 (11q14) and 932_f_8 (11q21).28 The relative positions of the 10p12 clones as indicated at the Human Genome Project working draft at UCSC (http://genome.ucsc.edu/) were verified by fiber-FISH.29
RT-PCR, cloning and sequencing
Total RNA was extracted from bone marrow using Trizol (Gibco BRL, Paisley, UK) according to the protocol of the manufacturer. cDNA was prepared from 1 μg RNA using random hexamers (100 ng) and the Superscript II reverse transcriptase kit (Life Technologies, Paisley, UK). Two μl of the reverse transcription reaction was used for PCR in a total volume of 50 μl using 10 × Boehringer buffer (Roche Diagnostics, Brussels, Belgium), 200 μM of each dNTP, 25 μM of each primer and 1 U of Platinum Taq polymerase (Gibco BRL). The primers AF10 pmr 29, AF10 pmr 18, AF10 pmr 41 and MLL exon5(b) for the detection of MLL/MLLT10 were described previously.14 For the identification of CALM/MLLT10 and MLLT10/CALM the primer combinations C-S1/A-A1, C-S1/A-A2 and C-A1/A-S1 were used.30 Samples were cycled in a Biozym PTC-200 for 40 cycles (denaturation, 92°C for 30 s; annealing, 57°C for 30 s; elongation, 72°C for 1 min). Agarose gel-sized and purified PCR products were cloned into pCR2.1-TOPO using the TOPO TA Cloning kit (Invitrogen, Paisley, UK), and inserts were sequenced on an ABI PRISM 377 sequencer (PE Biosystems Europe, Lennik, Belgium), using specific M13 forward and reversed primers (Invitrogen) and the Big Dye Terminator Sequencing Kit.
Cytogenetic and FISH analysis
Cytogenetic analysis at diagnosis revealed trisomy 8 and a chromosome 10;11 rearrangement in all 30 cells analysed (Figure 1a). The constitutional karyotype was normal. FISH analyses with chromosome 10 and 11 libraries and a chromosome 11 library in combination with a subtelomeric probe for 10p both demonstrated insertion of chromosome 11 material into the short arm of chromosome 10 (Figure 2a,b). Dual-color FISH was performed using YACs 742_f_9 and 856_b_9 covering the MLL gene and YAC 807_b_3 spanning the MLLT10 gene (Figure 2c). Hybridization signals for MLL and MLLT10 probes were localized on two regions, one proximal and one distal on the short arm of chromosome 10. No signals were observed for MLL on the derivative chromosome 11. Further characterization was done by four-color FISH using the MLL dual-color probe (Vysis), MLLT10 YAC 807_b_3 and 2 YACs located at 11q14 and 11q21 region, respectively (Figure 2d). The MLL spanning probes were split: the probe proximal to MLL and covering the 5′ part of MLL colocalized with the MLLT10 probe at the centromeric part of the insertion, whereas the 3′ part of MLL colocalized with the telomeric MLLT10 signal. One of the two proximal 11q YACs was inserted into 10p. Triple-color FISH with MLL (Vysis) in combination with YACs 946_f_4 and 932_f_8, showed that the 11q14 YAC 946_f_4 was retained on the der(11), whereas the 11q21 YAC 932_f_8 was inserted into 10p as expected from the previous in situ hybridization experiment (not shown). In order to generate the observed FISH data, we assumed that an inversion of 11q14-q23 with a breakpoint within the MLL gene occurred, followed by or accompanied by insertion of a larger part of 11q material (including 3′ MLL) into MLLT10 (Figure 3a).
Cytogenetic analysis at diagnosis revealed a del(9)(q12q34) and a t(10;11)(p12∼13;q23) in all 18 metaphases analysed (Figure 1b). FISH with MLL spanning probes revealed a split signal, with colocalization of the 5′ part of MLL and MLLT10 YAC 807_b_3 (Figure 2g). FISH with chromosome 10 and 11 libraries demonstrated an apparent reciprocal translocation (Figure 2f). No involvement of chromosome 9 could be demonstrated by dual-color FISH with chromosome 9 and 10 specific libraries (not shown). Triple-color FISH with a chromosome 10 specific library and MLL spanning probes showed translocation of 3′ MLL to chromosome 10p (Figure 2e). The MLLT10 YAC 807_b_3 was not split, but entirely translocated and colocalized to the der(11) 5′MLL (Figure 2g). In order to characterize the translocation in further detail, BAC clones RP11–418C1, RP11–177H22, RP11–249M6 and RP11–399C16, located in the genomic contig NT_008895 and covering MLLT10 and sequences immediately proximal and distal to MLLT10, were tested (see also Materials and methods). The relative positions of these clones are indicated at the Human Genome Project working draft at UCSC (http://genome.ucsc.edu/). Using fiber-FISH, we confirmed the positions as indicated (Figure 2j,k), and estimated the overlap of RP11–418C1 with RP11–177H22 to be less than 30 kb. RP11–418C1 and RP11–177H22 were translocated to the der(11) (Figure 2h). RP11–249M6 and RP11–399C16 were split and colocalized with 5′ and 3′ part of MLL dual-color probe (Figure 2i). RP11–251H5 located at 10p11.21 was retained on the der(10) as expected (not shown). These findings suggest that this 10;11 rearrangement resulted from an inversion of 3′ MLLT10 with breakpoints within MLLT10 and immediately proximal to MLLT10, followed by a reciprocal translocation involving MLL at 11q23 (Figure 3b).
RT-PCR, cloning and sequencing
Using primers AF10 pmr 29, AF10 pmr 18, AF10 pmr 41 and MLL exon5(b), RT-PCR reactions were performed for the detection of MLL/MLLT10 fusion transcripts, including positive controls. Using the AF10 pmr 29 and AF10 pmr 18 in combination with the primer MLL exon5(b), three bands were observed on agarose gel for both patients (Figure 4). Cloning and sequencing of these PCR products showed the presence of three distinct isoforms for MLL/MLLT10 fusion gene as the result of alternative splicing. The novel chromosomal breakpoint was located at cDNA position 883 (base position corresponding to the Genbank entry for MLLT10 accession number U13948) in MLLT10 and exon 8 in MLL. The second splice variant joined MLL exon7 and MLLT10-nt-883. In the third transcript, which also joined MLL exon7 and MLLT10-nt-883, exon 6 was spliced out. As expected, RT-PCR analyses for MLLT10-CALM and CALM-MLLT10 were negative in both patients.
Due to the opposite orientation of MLLT10 and MLL on their respective chromosome arms, MLL-MLLT10 gene fusion requires complex rearrangements with three or more breaks.8,9,10 Similar observations were made for other chromosomal abnormalities involving genes with opposite orientation, including EWS-ERG31 and ETV6-ABL.32 For the latter, we recently described two novel types of chromosomal rearrangements leading to ETV6-ABL fusion.25 Although these complex rearrangements may be readily visible at the cytogenetic level, in some instances the chromosomal defect may be subtle or even cryptic.13,25,33
fn5 Using multicolor FISH with locus-specific probes, we have investigated the chromosomal nature of two MLL-MLLT10-positive chromosome 10;11 rearrangements. In the first patient, at least four breakpoints must have occurred in order to explain the observed FISH results. In this patient, cytogenetic and FISH results demonstrated insertion of 11q material into 10p. More detailed analysis showed that in a first event an inversion with breakpoint in MLL and a proximal breakpoint in 11q14∼21 occurred. As the 3′ MLL part was present on the inserted 11q− material, we must however assume that a third breakpoint occurred distal to MLL prior to insertion of the 11q− segment into 10p12. This rearrangement resembles the inversion–insertion reported in patient 8 by Beverloo et al8 and the patient described by Tanabe et al10 In patient 2, reversed orientation of 3′ part of MLLT10 resulted from inversion on 10p with breakpoints within MLLT10 and immediately proximal to MLLT10, followed by a reciprocal translocation with MLL at 11q23. This alteration resembles the chromosomal abnormality in patient 4 described by Beverloo et al.8 This is the first report which indicates that the proximal inversion breakpoint is located immediately centromeric to MLLT10 at a distance less than 100 kb. The breakpoint region contains a predictive gene, DNAJL1. It remains to be elucidated whether the same breakpoint region is involved in other patients with this type of chromosomal rearrangement, leading to MLL-MLLT10 fusion. Also, possible involvement of DNAJL1 in these rearrangements should be investigated. Cloning of these breakpoints should also shed light on the mechanisms leading to these complex chromosomal rearrangements.
Review of the literature yielded 27 patients with MLL involved in 10;11 rearrangements, of which 20 had MLL-MLLT10 rearrangement as detectable with FISH or RT-PCR. In 13 patients, molecular cytogenetic analysis was performed which provided information concerning the nature of the chromosomal alteration (Table 1). These rearrangements can be classified into four different types of chromosomal rearrangements. In all types an inversion of the 5′ MLL or 3′ MLLT10 is required in order to allow an in-frame MLL-MLLT10 fusion. In the first two types, an inversion of the 11q− segment including 5′ MLL is followed by either translocation with (type 1) or insertion into (type 2) the short arm of chromosome 10 at 10p12. In the second two types a similar sequence occurred but here the orientation of the 3′ MLLT10 segment is inverted, followed by 11q23− translocation (type 3) or insertion (type 4) (Figure 5). Until now, four 10;11 rearrangements have been described in which a third chromosome is involved in the translocation.8,9,14 These translocations could be considered as either type 1 or type 3 variants (Table 1, cases 3, 6, 9 and 11). The 10;11 rearrangement in patient 1 of this report could be considered as a variant type 2 rearrangement, as an additional breakpoint distal to MLL occurred, following the inversion of 11q and prior to the insertion into MLLT10. The rearrangement in patient 2 resembles a type 3 rearrangement.
Yet another 10;11 chromosomal rearrangement has been described by Sinclair et al34 resulting in translocation of the entire MLL gene to distal 10p (10p15) followed by inversion with breakpoints at 10p12 and the translocated MLL. This could possibly be a fifth chromosomal mechanism leading to MLL-MLLT10. However, the fusion transcript has not been confirmed by FISH or RT-PCR in this patient.
Although molecular cytogenetic investigations provide insight into the detailed nature of chromosomal abnormalities, the mechanisms that trigger the formation of these alterations remain unclear. For some MLL aberrations, evidence was obtained that ALU repeat sequences, as well as topoisomerase cleavage sites and DNase I hypersensitive sites were implicated. It was demonstrated that the genomic breakpoints in MLL were located preferentially in the 5′ half of the breakpoint cluster region in de novo leukemia patients, whereas in therapy-related and infant leukemia the break is more frequently in the 3′ half of the breakpoint region containing the topoisomerase cleavage sites.35,36,37,38,39 Molecular analysis of the breakpoints occurring in these 10;11 rearrangements is required to understand how these complex rearrangements come about. Only one study thus far reported additional breakpoint analysis.17 FM3 sequences were cloned at the inversion breakpoint distal to MLLT10 and some homology to the consensus topoisomerase 2 binding site was found.
RT-PCR analysis for detection of MLL-MLLT10 fusion transcripts revealed a previously unreported MLL-exon-8-MLLT10 fusion and two smaller isoforms due to alternative splicing. A complex pattern of alternative splicing with exon scrambling has been reported for the MLL gene in both normal and malignant cells.40,41,42 Alternative splicing and cryptic splice site activation during RNA processing of MLL-AF4 chimeric transcripts has been observed.43 Recently, splice variants for MLL-MLLT10 fusion transcripts were also reported by Angioni et al.11 Clearly, alternative splicing of the normal MLL gene may result in increased complexity of the biological function of MLL and possibly the same holds for the splice variants of the hybrid transcripts.
In conclusion, multicolor FISH was successfully applied in the characterization of MLL-MLLT10-positive 10;11 chromosomal rearrangements. We described an as yet unreported chromosomal mechanism, leading to MLL-MLLT10 in-frame fusion. We also investigated an apparent reciprocal 10;11 rearrangement in further detail and compared our results with previously reported cases.
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FWO grant Nos G.0028.00 and G.0310.01 and BOF grant No. 011D7699. Heidi Van Limbergen is the recipient of a research grant of the University of Ghent. Bruce Poppe is supported by a grant of the Fund for Scientific Research, Flanders, Belgium (FWO-Vlaanderen).
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Van Limbergen, H., Poppe, B., Janssens, A. et al. Molecular cytogenetic analysis of 10;11 rearrangements in acute myeloid leukemia. Leukemia 16, 344–351 (2002) doi:10.1038/sj.leu.2402397
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Oncology Letters (2017)
A new rearrangement giving rise to a very rare MLL-MLLT10 fusion mRNA in an infant acute myeloid leukemia
Cancer Genetics (2015)