Analysis of the joining sequences of the t(15;17) translocation in human acute promyelocytic leukemia: Sequence non‐specific recombination between the <i>pml</i> and <i>rara</i> genes within identical short stretches

Yoshida, Hitoshi; Naoe, Tomoki; Fukutani, H; Kiyoi, Hitoshi; Kubo, Kazuaki; Ohno, Ryuzo

doi:10.1002/gcc.2870120107

Cited by 40 publications

(30 citation statements)

References 29 publications

(32 reference statements)

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“…Nevertheless, the presence of extra nucleotides inserted between FUS and CHOP sequences suggests that the formation of a hybrid FUS/ CHOP gene is not a simple strand break and ligation event. Similar insertion of extra nucleotides has previously been reported for PML/RARA in acute promyelocytic leukemia (Yoshida et al, 1995).…”

Section: An Octamer (Gc[a/t]gg[a/t]gg) Similar To the Chi (Gctggtggsupporting

confidence: 86%

“…The breakpoints could not be precisely determined in three cases (the AML, and MLS cases L1686 and 1955 ± 91) as a result of 1, 2 and 6, respectively, nucleotide matches between the contributing germline sequences. Similar ®ndings were previously reported from the breakpoints of the human hybrid genes TPR/ MET, RET/PTC, PML/RARA and ESW/FLI1 (Bhagirath et al, 1995;Dean et al, 1987;Smanik et al, 1995;Yoshida et al, 1995). Whether or not this feature is signi®cant for somatic recombinations is unknown.…”

Section: An Octamer (Gc[a/t]gg[a/t]gg) Similar To the Chi (Gctggtggsupporting

confidence: 75%

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Characteristic sequence motifs at the breakpoints of the hybrid genes FUS/CHOP, EWS/CHOP and FUS/ERG in myxoid liposarcoma and acute myeloid leukemia

et al. 1997

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We have sequenced the breakpoint regions in one acute myeloid leukemia (AML) with t(16;21)(p11;q22) resulting in the formation of a FUS/ERG hybrid gene and in four myxoid liposarcomas (MLS), three of which had the translocation t(12;16) (q13;p11) and a FUS/CHOP fusion gene and one with t(12;22;20)(q13;q12;q11) and an EWS/CHOP hybrid gene. The breakpoints were localized to intron 7 of FUS, intron 1 of CHOP, an intronic sequence of ERG and intron 7 of EWS. In two MLS cases with t(12;16) and in the AML, the breaks in intron 7 of FUS had occurred close to each other, a few nucleotides downstream from a TG dinucleotide repeat region. The break in the two MLS had occurred in the same ATGGTG hexamer and in the AML 40 nucleotides upstream from the hexamer. The third case of t(12;16) MLS had a break upstream and near a TCdinucleotide repeat region and a sequence similar to the chi bacterial recombination element was found tō ank the breakpoint. In the MLS with the EWS/ CHOP hybrid gene, the break in intron 7 of EWS had occurred close to an Alu sequence. Similarly, in all 4 MLS, the breaks in intron 1 of CHOP were near an Alu sequence. No Alu or other repetitive sequences were found 250 bp upstream or downstream from the break in the ERG intron involved in the AML case. In the AML, the MLS with ESW/CHOP and in one MLS with FUS/CHOP there were one, two and six, respectively, nucleotide identity between the contributing germline sequences in the breakpoint. In the other two MLS cases, two and three extra nucleotides of unknown origin were inserted between the FUS and CHOP sequences. At the junction and/or in its close vicinity, identical oligomers, frequently containing a trinucleotide TGG, were found in both partner genes. Our data thus show that all four genes-FUS, EWS, CHOP and ERG-contain characteristic motifs in the breakpoint regions which may serve as speci®c recognition sites for DNA-binding proteins and have functional importance in the recombination events taking place between the chromosomes. Di erent sequence motifs may, however, play a role in each individual case.

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Section: An Octamer (Gc[a/t]gg[a/t]gg) Similar To the Chi (Gctggtggsupporting

confidence: 86%

Section: An Octamer (Gc[a/t]gg[a/t]gg) Similar To the Chi (Gctggtggsupporting

confidence: 75%

Characteristic sequence motifs at the breakpoints of the hybrid genes FUS/CHOP, EWS/CHOP and FUS/ERG in myxoid liposarcoma and acute myeloid leukemia

et al. 1997

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“…Therefore, we used the NB4 cell line as an in vitro model. In NB4, the RARA breakpoint maps to nt 16268 (GenBank accession number: AJ297538), 31 meaning that the RARA gene is fused to the PML gene from nt 16269 onwards. The RARA P2 promoter, which maps to nts 619-10300, resides in the reciprocal RARA/ PML gene and can no longer control the production of an intact RARa (Figure 1a).…”

Section: Discussionmentioning

confidence: 99%

Aberrant promoter methylation of the retinoic acid receptor alpha gene in acute promyelocytic leukemia

et al. 2005

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The retinoic acid receptor alpha (RARA) gene is disrupted by PML/RARA fusion in acute promyelocytic leukemia (APL). The P2 promoter of RARA, controlling the RARa2 isoform, contains an RA-responsive element and may be targeted in APL. To test whether aberrant methylation of P2 was involved, 47 APL at diagnosis, 16 APL at first relapse, 50 acute myeloid leukemia (AML) and 22 acute lymphoblastic leukemia (ALL) were tested by methylation-specific polymerase chain reaction. RARA P2 methylation was highly associated with APL (APL: 25/63 vs AML/ALL: 2/75, Po0.0001). P2 methylation occurred at similar frequencies in APL at diagnosis and relapse, suggesting it was an initiating leukemogenic event. In the APL line NB4, RARa2 was not expressed, with the untranslocated RARA shown to be P2 methylated. 5-Azacytadine treatment of NB4 led to progressive P2 demethylation and re-expression of RARa2, confirming that RARA methylation collaborated with PML/RARA in totally suppressing RARa. In APL, RARA P2 methylation was unrelated to gender, age, presenting leukocyte counts and additional cytogenetic aberrations. For APL patients receiving all-trans retinoic acid for induction, P2 methylation did not affect the complete remission rates and survivals. RARA is the first myeloid-specific transcription factor shown to be dysregulated by both translocation and aberrant methylation.

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“…This complexity of the breakpoints is shared by MLL-AF4, TEL-AML1, PML-RARA, and CBFB-MYH11, translocations which occur in pediatric ALL as well as AML. [14][15][16]22,[55][56][57] These translocations like AML-ETO in children are not associated with etiologic causal agents in the vast…”

Section: Discussionmentioning

confidence: 99%

“…[6][7][8][9][10][11][12] Progress in characterizing the majority of leukemia translocations has been slower due to dispersed nature of the chromosomal fusions and difficulties in sequencing translocations because of large intronic regions; however, large-scale sequencing efforts have recently been undertaken. [13][14][15][16][17] The only pediatric translocation to date with hypothesized etiologies are the MLL fusions in infant leukemia, in which topoisomerase II inhibition by environmental and dietary agents may play a role. [18][19][20] The most common rearrangement in childhood leukemias is t(12;21)TEL-AML1, and we and others have noted structural features of the introns that may contribute to genomic breakage and refusion, including unstable repeat sequences and signs of non-homologous end joining repair.…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of genomic AML1-ETO fusions in childhood leukemia

et al. 2001

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T(8;21) AML1(CBFA2)-ETO(MTG8)is the most common chromosomal translocation in acute myeloid leukemia (AML) in both children and adults. We sought to understand the structure and gain insight into the fusion process between AML1 and ETO by sequencing genomic fusions in 17 primary childhood AMLs and two cell lines with t(8;21). Reciprocal translocations were sequenced for seven of the 19 samples. We assumed a null hypothesis that the translocation breakpoints would be evenly distributed along the intronic breakpoint cluster regions. Testing for multimodality via smoothed bootstrap statistical methods suggested, however, the presence of two separate cluster regions within both the AML1 and ETO breakpoint cluster regions. ETO breakpoints were predominantly located in intron 1B in a defined cluster 5Ј of exon 1A (scan statistic P value = 0.00001). All patients with available RNA expressed an AML1-ETO mRNA fusion between exon 5 of AML1 and exon 2 of ETO. Since the structural restraints for the fusion protein of AML1-ETO exclude exon 1A, we reason that ETO intron 1B harbors a structural feature with propensity for breakage and/or recombination. Chromosomal breakpoints displayed evidence of fusion by a non-homologous end joining process, with microhomologies and nontemplate nucleotides at some fusion junctions. Breakpoints in general displayed similar complexity of duplications, deletions, and insertions to other common pediatric leukemia translocations (TEL-AML1, MLL-AF4, PML-RARA, CBFB-MYH11) that we and others have analyzed. Leukemia (2001Leukemia ( ) 15, 1906Leukemia ( -1913

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Analysis of the joining sequences of the t(15;17) translocation in human acute promyelocytic leukemia: Sequence non‐specific recombination between the pml and rara genes within identical short stretches

Cited by 40 publications

References 29 publications

Characteristic sequence motifs at the breakpoints of the hybrid genes FUS/CHOP, EWS/CHOP and FUS/ERG in myxoid liposarcoma and acute myeloid leukemia

Characteristic sequence motifs at the breakpoints of the hybrid genes FUS/CHOP, EWS/CHOP and FUS/ERG in myxoid liposarcoma and acute myeloid leukemia

Aberrant promoter methylation of the retinoic acid receptor alpha gene in acute promyelocytic leukemia

Molecular characterization of genomic AML1-ETO fusions in childhood leukemia

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