FISH mapping of Philadelphia negative BCR/ABL1 positive CML

Virgili, Anna; Brazma, Diana; Reid, Alistair; Howard-Reeves, Julie; Valgañón, Mikel; Chanalaris, Anastasios; Melo, Valeria; Marín, David; Apperley, Jane F.; Grace, Colin; Nacheva, E.

doi:10.1186/1755-8166-1-14

Cited by 35 publications

(22 citation statements)

References 31 publications

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“…was carried out for further verification of the aCGH results to identify the genome aberrations at a cellular level using Bacterial Artificial Chromosomes (BAC) clones obtained from the BACPAC Resources Center (Children's Hospital Oakland Research Institute, Oakland, CA, USA), the Sanger Centre (Cambridge, U) and Invitrogen (Paisley, UK) following protocols in routine use [31]. Where possible a minimum of 100 interphase and 50 metaphase cells were screened with a dual colour dual FISH assay using BAC/fosmid probes selected for optimal coverage of the regions of I KZF1, CDKN2A, MLLT3, PAX5, PDCD1LG2 and JMJD2C genes.…”

Section: Methodsmentioning

confidence: 99%

Deletions of Immunoglobulin heavy chain and T cell receptor gene regions are uniquely associated with lymphoid blast transformation of chronic myeloid leukemia

Nacheva¹,

Brazma²,

Virgili³

et al. 2010

BMC Genomics

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BackgroundChronic myelogenous leukemia (CML) results from the neoplastic transformation of a haematopoietic stem cell. The hallmark genetic abnormality of CML is a chimeric BCR/ABL1 fusion gene resulting from the Philadelphia chromosome rearrangement t(9;22)(q34;q11). Clinical and laboratory studies indicate that the BCR/ABL1 fusion protein is essential for initiation, maintenance and progression of CML, yet the event(s) driving the transformation from chronic phase to blast phase are poorly understood.ResultsHere we report multiple genome aberrations in a collection of 78 CML and 14 control samples by oligonucleotide array comparative genomic hybridization. We found a unique signature of genome deletions within the immunoglobulin heavy chain (IGH) and T cell receptor regions (TCR), frequently accompanied by concomitant loss of sequences within the short arm regions of chromosomes 7 and 9, including IKZF1, HOXA7, CDKN2A/2B, MLLT3, IFNA/B, RNF38, PAX5, JMJD2C and PDCD1LG2 genes.ConclusionsNone of these genome losses were detected in any of the CML samples with myeloid transformation, chronic phase or controls, indicating that their presence is obligatory for the development of a malignant clone with a lymphoid phenotype. Notably, the coincidental deletions at IGH and TCR regions appear to precede the loss of IKZF1 and/or p16 genes in CML indicating a possible involvement of RAG in these deletions.

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Section: Methodsmentioning

confidence: 99%

Deletions of Immunoglobulin heavy chain and T cell receptor gene regions are uniquely associated with lymphoid blast transformation of chronic myeloid leukemia

Nacheva¹,

Brazma²,

Virgili³

et al. 2010

BMC Genomics

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“…The dual colour FISH assay that we designed and initially tested in all samples contained the BAC clones RP11-83J21 and RP11-323H21; the former targets the 3' end of ABL1 gene incorporating the whole of the coding region at 9q34.12 and was thus selected to detect the BCR/ABL1 fusion gene, while the latter targets a region 730 Kb downstream of the ABL1 gene and is present within the proximal breakpoint cluster region as identified in Ph negative BCR/ABL1 positive CML [13]. Each sample was initially tested with this dual FISH probe set to screen for differences between the two Ph chromosomes with emphasis on gains of ABL1 and the 9q34.12-q34.13 regions.…”

Section: Discussionmentioning

confidence: 99%

Genomic amplification of BCR/ABL1 and a region downstream of ABL1 in chronic myeloid leukaemia: a FISH mapping study of CML patients and cell lines

Virgili

Nacheva

2010

Mol Cytogenet

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BackgroundChronic myeloid leukaemia (CML) is characterized by the expression of the BCR/ABL1 fusion gene, a constitutively activated tyrosine kinase that commonly results from the formation of the Philadelphia (Ph) chromosome after a t(9;22)(q34;q11) or variant rearrangement. The duplication of the Ph chromosome is a recurring abnormality acquired during disease progression, whereas intrachromosomal amplification of BCR/ABL1 is a rare phenomenon and has been associated with imatinib therapy resistance. Archival bone marrow chromosome suspensions from 19 CML patients known to carry more than 1 copy of BCR/ABL1 and 10 CML cell lines were analyzed by fluorescent in situ hybridization with a panel of probes from 9q34.1-qter to investigate whether they carried two identical copies of the Ph chromosome or, instead, one or both Ph contained cryptic imbalances of some regions.ResultsA duplication of the entire Ph chromosome with no further events involving the derivative 22 was found in 12 patients. In contrast, a sideline with either 1 or 2 isochromosomes of the Ph chromosome was identified in 6 patients but none of the cell lines. In one of the patients a translocation between the distal end of one arm of the isoderivative chromosome 22 and a third chromosome was revealed. 2 patients were found to carry marker structures harbouring high copy number gains of BCR/ABL1 fusion along with a variable part of 9q34 region downstream of ABL1 breakpoint, similarly to the markers present in the imatinib resistant cell line K562. We identified the following regions of amplification: 9q34.1 → q34.2 and 9q34.1 → qter, with a common minimum amplified region of 682 Kb. One of the patients had 5 BCR/ABL1 positive clones with variable level of 9q34 amplifications on a variety of structures, from an isoderivative 22 to tandem duplications.ConclusionsThese data confirm that the intrachromosomal genomic amplification of BCR/ABL1 that occurs in some CML patients during disease progression also involves amplification of 9q34 gene-rich sequences downstream of ABL1 breakpoint. The variety of rearrangements identified in this relatively small cohort demonstrates that the Ph chromosome is not a stable structure but prone to further rearrangements during disease progression.

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“…Although rare, approximately 1% of all BCR-ABL1-positive chronic myeloid leukemia cases have a cytogenetically cryptic BCR-ABL1 gene rearrangement that has arisen through insertion or other, more complex, means. 19 Insertional events are not restricted to BCR-ABL1, they have been reported for many genes, including KMT2A and others. 20 Another possibility is that there has been a classic t(9;22)(q34;q11.2), with a deletion of BCR from 1 derivative chromosome; however, this was not observed by conventional cytogenetics as both chromosomes 9 and 22 were apparently normal.…”

Section: Discussionmentioning

confidence: 99%

BCR-ABL1 gene rearrangement as a subclonal change in ETV6-RUNX1–positive B-cell acute lymphoblastic leukemia

et al. 2016

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Key Points• BCR-ABL1 rearrangement as a subclonal change in ETV6-RUNX1-positive B-ALL is a rare occurrence not previously reported.• The prognosis of this rare subclonal change has not been determined, yet inclusion of tyrosine kinase inhibitors in treatment is ubiquitous.We report here on a case of ETV6-RUNX1-positive B-cell acute lymphoblastic leukemia (B-ALL) that has acquired a BCR-ABL1 gene rearrangement as a subclonal change. The 19-year-old female patient presented with B symptoms, pancytopenia, and circulating blasts.The bone marrow aspirate was hypercellular and was infiltrated by an immature blast population that was confirmed as B-ALL by flow cytometry. Sequential fluorescent in situ hybridization was performed on the patient's leukemic cells, which were shown to contain both ETV6-RUNX1 and BCR-ABL1 gene rearrangements. The majority of nuclei (85%) showed only the ETV6-RUNX1 gene rearrangement; however, an additional 10% also showed a variant BCR-ABL1 gene rearrangement, indicating the ETV6-RUNX1 gene rearrangement was the primary change. A review of the literature has shown that acquisition of a BCR-ABL1 gene rearrangement as a secondary change in B-ALL is a very rare occurrence, and the effect it may have on prognosis is uncertain in the modern therapy age.

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FISH mapping of Philadelphia negative BCR/ABL1 positive CML

Cited by 35 publications

References 31 publications

Deletions of Immunoglobulin heavy chain and T cell receptor gene regions are uniquely associated with lymphoid blast transformation of chronic myeloid leukemia

Deletions of Immunoglobulin heavy chain and T cell receptor gene regions are uniquely associated with lymphoid blast transformation of chronic myeloid leukemia

Genomic amplification of BCR/ABL1 and a region downstream of ABL1 in chronic myeloid leukaemia: a FISH mapping study of CML patients and cell lines

BCR-ABL1 gene rearrangement as a subclonal change in ETV6-RUNX1–positive B-cell acute lymphoblastic leukemia

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