Exon/intron structure of the human ALL‐1 (MLL) gene involved in translocations to chromosomal region 11q23 and acute leukaemias

Nilson, I.; Löchner, Klaus; Siegler, G.; Greil, Johann; Beck, J. D.; Fey, Georg H.; Marschalek, Rolf

doi:10.1046/j.1365-2141.1996.d01-1748.x

Cited by 124 publications

(92 citation statements)

References 20 publications

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“…The MLL/AF-4 mRNA of patient PCB contained a fusion of MLL exon 11 to AF-4 exon 4 (nomenclature according Nilson et al, 1996Nilson et al, , 1997Marschalek et al, 1997). The AF-4/MLL mRNA of the same patient showed a fusion of AF-4 exon 3 to MLL exon 12.…”

Section: Mapping Of Both Translocation Breakpoints For Three Additionmentioning

confidence: 97%

“…Breakpoints from patients (circled numbers or letters) were analysed as described in the text and are connected by lines between both breakpoint cluster regions. Numbering of exons of the MLL gene according to Nilson et al (1996) and Marschalek et al (1997); of the AF-4 gene according to Nilson et al (1997) cross-over mechanism could have produced the observed ®nal state. Each of these translocation events was accompanied by deletions, duplications and/or inversions of germline DNA sequences.…”

Section: Characteristic Duplications Deletions and Inversions Are Prmentioning

confidence: 99%

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A DNA damage repair mechanism is involved in the origin of chromosomal translocations t(4;11) in primary leukemic cells

et al. 1999

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Some chromosomal translocations involved in the origin of leukemias and lymphomas are due to malfunctions of the recombinatorial machinery of immunoglobulin and Tcell receptor-genes. This mechanism has also been proposed for translocations t(4;11)(q21;q23), which are regularly associated with acute pro-B cell leukemias in early childhood. Here, reciprocal chromosomal breakpoints in primary biopsy material of fourteen t(4;11)-leukemia patients were analysed. In all cases, duplications, deletions and inversions of less than a few hundred nucleotides indicative of malfunctioning DNA repair mechanisms were observed. We concluded that these translocation events were initiated by several DNA strand breaks on both participating chromosomes and subsequent DNA repair by`error-prone-repair' mechanisms, but not by the action of recombinases of the immune system.

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Section: Mapping Of Both Translocation Breakpoints For Three Additionmentioning

confidence: 97%

Section: Characteristic Duplications Deletions and Inversions Are Prmentioning

confidence: 99%

A DNA damage repair mechanism is involved in the origin of chromosomal translocations t(4;11) in primary leukemic cells

et al. 1999

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“…There are two numbering systems of exons; the most recent system will be used in this report ( Figure 4). 59 The MLL protein contains a region of three AT-hooks, which have binding capacity to the minor groove of DNA. A domain with binding capacity to hemimethylated DNA is located in the 5Ј portion of the protein encoded by exon 8.…”

Section: Testing and Standardization Proceduresmentioning

confidence: 99%

True

1999

Leukemia

136

110

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Prospective studies on the detection of minimal residual disease (MRD) in acute leukemia patients have shown that largescale MRD studies are feasible and that clinically relevant MRDbased risk group classification can be achieved and can now be used for designing new treatment protocols. However, multicenter international treatment protocols with MRD-based stratification of treatment need careful standardization and quality control of the MRD techniques. This was the aim of the European BIOMED-1 Concerted Action 'Investigation of minimal residual disease in acute leukemia: international standardization and clinical evaluation' with participants of 14 laboratories in eight European countries (ES, NL, PT, IT, DE, FR, SE and AT). Standardization and quality control was performed for the three main types of MRD techniques, ie flow cytometric immunophenotyping, PCR analysis of antigen receptor genes, and RT-PCR analysis of well-defined chromosomal aberrations. This study focussed on the latter MRD technique. A total of nine well-defined chromosome aberrations with fusion gene transcripts were selected: t(1;19) with E2A-PBX1, t(4;11) with MLL-AF4, t(8;21) with AML1-ETO, t(9;22) with BCR-ABL p190 and BCR-ABL p210, t(12;21) with TEL-AML1, t(15;17) with PML-RARA, inv (16) with CBFB-MYH11, and microdeletion 1p32 with SIL-TAL1. PCR primers were designed according to predefined criteria for single PCR (external primers A ↔ B) and nested PCR (internal primers C ↔ D) as well as for 'shifted' PCR with a primer upstream (E5Ј primer) or downstream (E3Ј primer) of the external A ↔ B primers. The 'shifted' E primers were designed for performing an independent PCR together with one of the internal primers for confirmation (or exclusion) of positive results. Various local RT and PCR protocols were compared and subsequently a common protocol was designed, tested and adapted, resulting in a standardized RT-PCR protocol. After initial testing (with adaptations whenever necessary) and approval by two or three laboratories, the primers were tested by all participating laboratories, using 17 cell lines and patient samples as positive controls. This testing included comparison with local protocols and primers as well as sensitivity testing via dilution experiments. The collaborative efforts resulted in standardized primer sets with a minimal target sensitivity of 10 −2 for virtually all single PCR analyses, whereas the nested PCR analyses generally reached the minimal target sensitivity of 10 −4 . The standardized RT-PCR protocol and primer sets can now be used for molecular classification of acute leukemia at diagnosis and for MRD detection during follow-up to evaluate treatment effectiveness. Keywords: acute myeloid leukemia (AML); acute lymphoblastic leukemia (ALL); PCR; standardization; fusion genes; chromosome PrefaceMonitoring of acute leukemia patients during and after treatment for the presence of remaining leukemic cells ('minimal residual disease', MRD) has been shown to give major insight into the effectiveness of treatment. [1...

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“…16 Primer sequences are listed in Table 1. Nucleotide and exon numbers are per Chaplin et al 11 for AF10 and Nilson et al 26 for MLL. To confirm the integrity of isolated RNA, a portion of Abl cDNA was amplified using previously described primers.…”

Section: Molecular Analysesmentioning

confidence: 99%

Protean clinical manifestations in children with leukemias containing MLL-AF10 fusion

et al. 2000

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Translocations involving the MLL gene on chromosome 11q23 occur in 5-10% of human leukemias, and involve fusion with more than 30 different partner genes. The MLL-AF10 fusion produced by the t(10;11)(p12;q23) or ins(10;11)(p12;q23q13) occurs in a small percentage of acute leukemias, most commonly acute myelogenous leukemia (AML) of the M5 FAB subtype. We report two cases of AML (M5a and M0) and one case of acute lymphoblastic leukemia containing MLL-AF10 fusion. Each case had varied clinical characteristics, despite expressing similar MLL-AF10 fusion transcripts. Including the three cases described in this report, we identified a total of 38 cases of leukemia with MLL-AF10 fusion. Approximately one-third of these are not M5 AML. Taken together, these findings emphasize that while the sentinel molecular event may be identical in a disease, the clinical presentation and outcome can vary widely.

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Exon/intron structure of the human ALL‐1 (MLL) gene involved in translocations to chromosomal region 11q23 and acute leukaemias

Cited by 124 publications

References 20 publications

A DNA damage repair mechanism is involved in the origin of chromosomal translocations t(4;11) in primary leukemic cells

A DNA damage repair mechanism is involved in the origin of chromosomal translocations t(4;11) in primary leukemic cells

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Protean clinical manifestations in children with leukemias containing MLL-AF10 fusion

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