Characterization of the translocation breakpoint sequences in philadelphia‐positive acute lymphoblastic leukemia

Papadopoulos, Panos; Greenstein, Amy; Gaffney, Robert A.; Westbrook, Carol A.; Wiedemann, Leanne M.

doi:10.1002/gcc.2870010308

Cited by 36 publications

(18 citation statements)

References 36 publications

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“…Alu interspersed sequence elements have been found close to or at the breakpoints in Philadelphia (Ph) chromosome positive chronic myeloid leukemia and acute lymphoblastic leukemia and may be involved in homologous or non-homologous recombinations leading to the formation of the Ph chromosome (de Klein et al, 1986;Papadopoulos et al, 1990) (Krowczynska et al, 1990). Finally, topoisomerase II may be involved.…”

Section: Resultsmentioning

confidence: 99%

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: Resultsmentioning

confidence: 99%

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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“…Experimental data implicate NHEJ, involving small deletions and microhomology, in the formation of chromosomal translocations (Varga and Aplan, 2005;Weinstock et al, 2006). In accordance, microhomology at the BCR/ABL junction region has been detected (Papadopoulos et al, 1990). HRR does not appear to be involved in the overwhelming majority Figure 2 Hypothetical mechanisms for the formation of reciprocal chromosomal translocations encoding FTKs.…”

Section: Aberrant Repair Of Dsbs Leading To Chromosomal Translocationsmentioning

confidence: 89%

Fusion tyrosine kinases: a result and cause of genomic instability

Penserga

Skórski

2006

Oncogene

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“…This finding suggests that Alu sequences may facilitate the BCR/ABL recombination process in variant translocations and provides intriguing evidence that these elements may play a direct role in the recombination process in BCR-ABL translocations. Sequence analysis of BCR-ABL and/or ABL-BCR recombination products from 21 standard t(9;22) rearrangements of CML 38,39 analysis of M-Bcr 40 as well as minor breakpoint 41,42 has provided indications that Alu repeat elements may play a role in the recombination process, since Alu elements were present at or adjacent to the breakpoints on the chromosome 22. Members of the Alu repetitive DNA family are often found at illegitimate junctions such as deletion or translocation breakpoints.…”

Section: Discussionmentioning

confidence: 99%

Primary chromosomal rearrangements of leukemia are frequently accompanied by extensive submicroscopic deletions and may lead to altered prognosis

Kolomietz

Al-Maghrabi

Brennan

et al. 2001

Blood

198

171

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BCR/ABL fluorescent in situ hybridization study of chronic myeloid leukemia (CML) and Philadelphia ؉ (Ph ؉ ) acute lymphoid leukemia (ALL) indicated that approximately 9% of patients exhibited an atypical hybridization pattern consistent with a submicroscopic deletion of the 5 region of ABL and the 3 region of the BCR genes on the 9q ؉ chromosome. The CML patients with deletions had a shorter survival time and a high relapse rate following bone marrow transplant. Since deletions are associated with both Ph ؉ CML and ALL, it seemed probable that other leukemia-associated genomic rearrangements may also have submicroscopic deletions. This hypothesis was confirmed by the detection of deletions of the 3 regions of the CBFB and the MLL genes in AML M4 patients with inv(16) and in patients with ALL and AML associated with MLL gene translocations, respectively. In contrast, analysis of the AML M3 group of patients and AML M2 showed that similar large deletions were not frequently associated with the t(15; 17) or t(8;21) translocations. Analysis of sequence data from each of the breakpoint regions suggested that large submicroscopic deletions occur in regions with a high overall density of Alu sequence repeats. These findings are the first to show that the process of deletion formation is not disease specific in leukemia and also implicate that the presence of repetitive DNA in the vicinity of breakpoint regions may facilitate the generation of submicroscopic deletions. Such deletions could lead to the loss of one or more genes, and the associated haploinsufficiency may result in the observed differences in clinical behavior. IntroductionSince the discovery of the Philadelphia (Ph) chromosome in patients with chronic myelogenous leukemia (CML), it has become evident that specific chromosomal rearrangements are consistently associated with hematologic malignancies. 1 Although it is well established that such recurrent chromosome translocations generate several different types of pathognomic fusion oncogenes, the precise details of the molecular processes leading to these rearrangements in leukemias are poorly understood.The Ph chromosome arises from a reciprocal translocation of the long arms of chromosomes 9 and 22 that transposes the 3Ј segment of the ABL gene from 9q34 to the 5Ј segment of the BCR gene on 22q11. The resulting BCR-ABL gene is transcribed into a chimeric messenger RNA and then translated into fusion proteins of varying size (p190 bcr-abl , p210 bcr-abl , and p230 bcr-abl ), depending on the location of the breakpoint of the genes involved. Although these BCR/ABL chimeric fusion proteins play a central role in the pathogenesis of CML, it is unclear whether these fusion oncoproteins alone are sufficient to explain the full range of clinical responses to the disease process. 2 Recently it was proposed that extensive submicroscopic deletions, 5Ј of ABL and 3Ј of BCR, on the derivative chromosome 9 could often accompany BCR/ABL rearrangement and that the disease associated with a deletion was more refractil...

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Characterization of the translocation breakpoint sequences in philadelphia‐positive acute lymphoblastic leukemia

Cited by 36 publications

References 36 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

Fusion tyrosine kinases: a result and cause of genomic instability

Primary chromosomal rearrangements of leukemia are frequently accompanied by extensive submicroscopic deletions and may lead to altered prognosis

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