FISH mapping of Philadelphia negative BCR/ABL1 positive CML
© Virgili et al; licensee BioMed Central Ltd. 2008
Received: 21 May 2008
Accepted: 18 July 2008
Published: 18 July 2008
Chronic myeloid leukaemia (CML) is a haematopoietic stem cell disorder, almost always characterized by the presence of the Philadelphia chromosome (Ph), usually due to t(9;22)(q34;q11) or its variants. The Ph results in the formation of the BCR/ABL1 fusion gene, which is a constitutively activated tyrosine kinase. Around 1% of CML patients appear to have a Ph negative karyotype but carry a cryptic BCR/ABL1 fusion that can be located by fluorescence in situ hybridisation (FISH) at chromosome 22q11, 9q34 or a third chromosome. Here we present FISH mapping data of BCR and ABL1 flanking regions and associated chromosomal rearrangements in 9 Ph negative BCR/ABL1 positive CML patients plus the cell line CML-T1.
BCR/ABL1 was located at 9q34 in 3 patients, 22q11 in 5 patients and CML-T1 and 22p11 in 1 patient. In 3 of 6 cases with the fusion at 22q11 a distal breakpoint cluster was found within a 280 Kb region containing the RAPGEF1 gene, while in another patient and the CML-T1 the distal breakpoint fell within a single BAC clone containing the 3' RXRA gene. Two cases had a duplication of the masked Ph while genomic deletions of the flanking regions were identified in 3 cases. Even more complex rearrangements were found in 3 further cases.
BCR/ABL1 formation resulted from a direct insertion (one step mechanism) in 6 patients and CML-T1, while in 3 patients the fusion gene originated from a sequence of rearrangements (multiple steps). The presence of different rearrangements of both 9q34 and 22q11 regions highlights the genetic heterogeneity of this subgroup of CML. Future studies should be performed to confirm the presence of true breakpoint hot spots and assess their implications in Ph negative BCR/ABL1 positive CML.
Chronic myeloid leukaemia (CML) is a pluripotent haematopoietic stem cell disorder defined by expression of the BCR/ABL1 fusion gene, a constitutively activated tyrosine kinase, harbored by the Philadelphia chromosome (Ph), which is a result of a t(9;22)(q34;q11) or a related variant translocation . In ~1% of the CML patients the bone marrow cells appear to be Ph negative by G-banding, although the BCR/ABL1 fusion gene can be identified by molecular means and located by fluorescence in situ hybridisation (FISH) on chromosome 22q11, 9q34 or even a third chromosome. The biology and clinical significance of the genetic rearrangements in Ph negative BCR/ABL1 positive disease have been widely discussed following the first descriptions [2–5]. Two mechanisms for the formation of the chimeric gene in masked Ph positive cells have been postulated: either by insertion of ABL1 into the BCR region (or vice versa) or by a multiple step model where a classical t(9;22) is followed by a translocation of both products and/or another autosome, thereby restoring the normal chromosome morphology. In both instances, more than the 2 breaks associated with classical t(9;22) are implicated. Although as early as 1990 Morris et al.  provided evidence that the insertion involves additional sequences distal to the 3' ABL1 site, the extent of the genomic rearrangements in this form of CML are unknown.
In view of the few studies published with a precise map of the insertions [7–10], we aimed to construct an accurate map of the insertions in the cell line CML-T1  and 9 patients with Ph negative BCR/ABL1 positive CML using a range of FISH probes obtained from BAC clones. The fusion gene was identified at 9q34 (3 patients), 22q11 (5 patients and CML-T1) and 22p11 (3 patients), resulting in relocation of sequences well in excess of either 3' ABL or 5' BCR by means of a direct insertion (6 patients and CML-T1) or a sequence of events (3 patients). Recurrent distal breakpoints were found at the regions of RAPGEF1 and RXRA genes.
Characteristics of the samples.
46, XX 
46, XX 
46, XX 
46, XX 
Cell line (CML-T1)
92 < 4n > XXX, t(6;7)(q24;q35)x2, del(11)
46, XX 
46, XX 
46, XX 
46, XX 
46, XX 
Summary of the BAC clones used for FISH analysis, their genomic address and source.
BACPAC (32K Clone Set)
BACPAC (32K Clone Set)
BACPAC (32K Clone Set)
BACPAC (32K Clone Set)
BACPAC (32 K Clone Set)
BACPAC (32 K Clone Set)
BACPAC (32 K Clone Set)
BACPAC (32 K Clone Set)
BACPAC (32 K Clone Set)
BACPAC (32 K Clone Set)
BAC RP11-164N13 was used to target BCR gene. Since this BAC covers both major and minor BCR breakpoints, it is found split when BCR gene is rearranged. RP11-61N10 covers BCR non-coding sequences centromeric to the breakpoint and it was used to identify 5' BCR region. RP11-83J21, which covers the 3' end of ABL1 incorporating the whole of the coding region, was used to identify the sequences telomeric of the ABL1 breakpoint, whereas RP11-57C19 was used to identify the ABL1 sequences centromeric of the breakpoint.
The BAC clones and genes were located according to the UCSC database, hg17 (University of California Santa Cruz, CA, USA) . Mapping data for the 32 K human clone set was obtained from the BACPAC Resources Center website  and used to assess the size of the sequences found to be rearranged. In addition, sub-telomeric probes directly labelled from the regions of 9q, 22q and 16q were used (Stretton Scientific Ltd, Stretton, UK). All tests were carried out as dual colour, dual probe FISH. Digital imaging and karyotyping were carried out using a SmartCapture and SmartType FISH workstation (Digital Scientific Ltd, Cambridge, UK).
Array CGH analysis (aCGH) was carried out on the cell line CML-T1. The aCGH was performed using two platforms – 1 Mb BAC clone chip (SGI2600)  and oligo-nucleotide (105 K Agilent)  following manifacturer's protocol, while data processing and presentations were carried out using 'in house' software as reported [18, 19].
FISH analysis using commercial BCR/ABL1 D-FISH probe (Vysis)
The BCR/ABL1 D-FISH probe (Vysis) contains sequences covering both genes labelled in different colours, so that rearrangements affecting them can be visualised at chromosome level. The ABL1 probe (red) targets a 650 Kb region of 9q34.1 including the whole of the ABL1 gene (173.8 Kb), thus spanning the common breakpoint, and extends 5' of ABL1 to incorporate the ASS gene. The BCR probe (green) is represented by two 600 Kb regions of 22q11.2 separated by a 300 Kb gap, one of the regions covering the entire BCR gene and extending 5' of it in order to include the IGLV gene, and the other starting 300 Kb telomeric of BCR and ending at 900 Kb 3' of the gene. The application of this probe revealed the BCR/ABL1 fusion at three different chromosome sites: at 22q11.2 (samples no 1–6), at 22p11 (sample no 7) and at 9q34 (samples no 8–10). There was evidence for the formation of the reciprocal ABL1/BCR fusion in just one patient (no 4), which showed 2 fusion signals at der(22) and der(9). In the remaining cases only 1 fusion signal was observed, irrespective of the fusion gene location.
In addition, D-FISH also revealed the presence of different clones with further rearrangements in CML-T1 and patients no 1 and 3. CML-T1 was found to harbour 3 clones: i) 7 out of 20 metaphases (35%) showed a 2 red 2 fusion signal pattern typical of diploid cells with duplication of the masked Ph and no normal 22 homologue (loss of the green signal); ii) 7 out of 20 metaphases (35%) showed a 4 red 4 fusion pattern for tetraploid cells with duplication of the masked Ph and no normal 22; iii) 6 out of 20 metaphases (30%) showed a 2 red 4 fusion pattern for tetraploid cells with duplication of the masked Ph, no normal 22 and deletion of 5' ABL1 (loss of two red signal). Patient no 3 had also developed a sub-clone with a duplication of the masked Ph and loss of the normal 22 homologue (2 red 2 fusion D-FISH pattern), as seen in 4 out of 20 metaphases (20%). On the other hand, D-FISH in patient no 1 showed a 1 red 1 green 1 fusion signal pattern, uncovering a deletion of sequences centromeric to ABL1 at the der(9)ins(22;9) in all cells screened (loss of 1 red signal).
Patients with BCR/ABL1 fusion residing on chromosome 22q11.2
The BAC clone RP11-83J21 covering 3' ABL1 moved to 22q11 in 6 cases (no 1–6), whereas RP11-57C19 remained at der(9) in all but one (no 1, Figure 1). In patient no 1, we identified a cryptic genome loss at der(9) of at least 1.34 Mb in all cells. The sequences deleted, centromeric of ABL1 breakpoint, were covered by the BAC clones RP11-57C19 to RP11-17O4. However, it was not possible to assess the full extend of the deletion due to lack of material.
Patient with the BCR/ABL1 fusion residing at 22p11
Patients with the BCR/ABL1 fusion residing at 9q34.1
In patient no 8, the insertion was accompanied in all cells by loss of a region at least 1.77 Mb long from 22q11.2 and immediately distal to the BCR breakpoint, covered from the 3' end of RP11-164N13 to at least RP11-765G14 (Figure 1).
Since the first description of a Ph negative BCR/ABL1 positive CML patient , several studies have been published reporting similar cases. Most of them are focused on the presence and location of the BCR/ABL1 fusion in CML patients with masked Ph chromosome and commonly achieved by application of commercial FISH probes, which have been proved to be very useful to identify the presence and location of the BCR/ABL1 fusion gene in CML patients with no distinguishable Ph chromosome. These studies have established the importance of FISH tests for the diagnosis and therapy monitoring of Ph negative BCR/ABL1 positive CML. However, the commercial probes don't provide enough information to understand the mechanisms involved in the formation of the masked Ph chromosome.
We used FISH mapping with BAC probes in order to study the formation of the BCR/ABL1 fusion and the underlying genomic rearrangements in 9 CML patients with Ph negative BCR/ABL1 positive CML and the cell line CML-T1. The formation of the fusion gene resulted from the relocation of not only the 3' ABL1 sequences within the BCR region at chromosome 22q11.2 or 5' BCR sequences within ABL1 region at 9q34.1, but also a considerable amount of flanking material, leaving the chromosome morphology apparently intact.
The fusion gene was located at 9q34.1 in 3 patients, at 22q11.2 in 5 patients and CML-T1, and at 22p11 in another patient. 5 out of the 6 cases with a 9q34 insertion at 22q11 displayed recurrent distal breakpoints that fell within two gene bearer regions. Thus, in 3 patients a common breakpoint cluster of 280 Kb was found. According to UCSC database, this region houses 3 genes: POMT1 (protein-O-mannosyltransferase1), UCK1 (uridine-cytidine kinase 1) and RAPGEF1 (guanine nucleotide releasing factor for RAP1; also known as C3G). In another patient and CML-T1 the breakpoint fell within a single BAC clone encompassing the 3' end of RXRA gene (retinoid × receptor alpha). Although further investigations were not carried out in this study, both RAPGEF1 and RXRA belong to pathways the disruption of which may be relevant to the evolution of the patients. RAPGEF1 has been shown to have transformation suppressor activity towards several oncogenes [20, 21] and also interact with BCR/ABL1 . RXRA belongs to a family of nuclear receptors that target multiple signalling pathways  and its downregulation has been showed to be critical for neutrophil granulocytes differentiation . Other studies found RXRA to contribute in acute promyelocytic leukaemia transformation [25, 26]. Although we have no direct evidence for the immediate involvement of either RAPGEF1 or RXRA genes, their potential role merits further investigation.
Two other mapping studies that found similar insertions have been published [7, 8]. In the first study, the authors used FISH mapping to identify the rearrangements involved in 2 Ph negative CML patients with variant translocations. A 3 Mb insertion from 22q11 into ABL1 was identified in 1 patient, while the other had a 9q34 insertion at the BCR region with a distal breakpoint falling within the clone RP11-353C22 (genome address: 31,278,002–131,588,248). This result matches with our findings since the latter BAC is located within the same 280 Kb common breakpoint region identified in 3 patients of our study. On the other hand, Valle et al.  found a 5.6 Mb insertion of 9q34 sequences into BCR. This insertion is larger than the ones identified in our study and was not accompanied by any deletions or other rearrangements.
Deletions of 5' ABL1 and/or 3' BCR sequences at the der(9) chromosome in patients with classical and variant Ph translocations  have been shown to have adverse prognostic value in CML patients treated with interferon , although their impact in patients being treated with tyrosine kinase inhibitors is controversial [29–31]. Dual colour, dual fusion translocation FISH probes spanning the BCR and ABL1 genes are very useful for revealing these events but they have a limited value in interphase nuclei in patients with masked Ph, since often the merging of the 5' BCR and 3' ABL1 signals by simple insertion leads to an apparent loss of one fusion signal that can be falsely assessed as deletion . Thus, D-FISH (Vysis) in a patient with a direct ins(22;9) gives a 2 red, 1 green, 1 fusion signal pattern, which is the same pattern obtained in case of a typical t(9;22) with deletion of 5' ABL1 at der(9). If the patient has a direct ins(9;22) the D-FISH signal pattern is 1 red, 2 green, 1 fusion, which could be mistaken for a typical t(9;22) with deletion of 3' BCR at der(9). Furthermore, Ph negative BCR/ABL1 positive patients with either a cryptic deletion of 5' ABL1 or 3' BCR show a 1 red, 1 green, 1 fusion D-FISH pattern, also typical for a t(9;22) with deletion of the reciprocal ABL1/BCR fusion. Therefore, when a deletion signal pattern is detected by interphase FISH with a dual colour, dual fusion probe, it is essential to look also at the metaphases in order to be able to differentiate a classical t(9;22) with deletion from a simple insertion.
Batista et al  reported a Ph negative BCR/ABL1 positive patient with an insertion of ABL1 into BCR associated with a deletion of the ASS – 5' ABL1 region. Zagaria et al  also reported two cases of CML patients with masked Ph and associated deletions: one patient with a cryptic ins(9;22) and a deletion of 5' ABL1 and 3' BCR regions; the other patient with a multi-step variant translocation and a deletion of around 400 Kb telomeric of the ABL1 gene. In addition to them, De Melo et al  identified with commercial triple-colour FISH probes 5' ABL1 deletions in 2 patients and 3' BCR deletion in 1 patient out of 14 CML patients with masked Ph. Our study confirmed and sized such deletions in 2 patients which where also part of De Melo's cohort. CML-T1 also had a 8.7 Mb deletion of 9q34 material in one of the sub-clones, but in this case the loss was found to affect the homologue not involved in the BCR/ABL1 formation.
We identified a duplication of the chromosome 22 harboring the BCR/ABL1 fusion accompanied by loss of the normal homologue in 1 out of 9 patients in this study plus the cell line CML-T1. Such duplications of the BCR/ABL1 bearing chromosome (either chromosome 22 or 9) seem to be a relatively common event in Ph negative BCR/ABL1 positive CML patients, being accompanied by loss of the normal homologue in most of the cases and seen both in chronic phase and blast crisis [33–35].
Regarding the formation of the fusion gene in Ph negative BCR/ABL1 positive CML patients, Morris et al  suggested two possible mechanisms: a one step model, where BCR/ABL1 results from a simple insertion of either 3' ABL1 into BCR or 5' BCR into ABL after three genomic breaks; and a multiple step model, with an initial classical t(9;22)(q34;q11) followed by a second translocation of both products and/or a third chromosome, requiring a minimum of 4 genomic breaks.
Our study provided evidence for the existence of both mechanisms implicated in the formation of the fusion gene in Ph negative patients. We found a simple insertion (one step event) in 6 out of 9 patients (no 1–3, 8–10) and CML-T1 (no 5), with no evidence of secondary rearrangements within the regions flanking BCR and ABL1 breakpoints apart from the accompanying deletions seen in 2 patients and CML-T1. On the other hand, traces of sequential rearrangements indicating a multiple step mechanism were found in 3 patients. Patient no 4 had a 9q34 insertion at chromosome 22 with bits from 22q11 distal to the breakpoint embedded within the der(9), suggesting an initial t(9;22)(q34;q11) followed by further translocation of both products. Patient no 7 carried the BCR/ABL1 fusion at 22p11. Sequences downstream of the breakpoint remained at their original location, while 5' BCR and all 9q34 sequences distal to ABL1 breakpoint (including the telomere) were relocated at 22p11, which could be explained by an initial t(9;22)(q34;q11) followed by a three-way translocation between 9q34, 22q11 and 22p11. This sequence of events would have required 5 breaks (2 for the translocation and 3 for the second one). However, an initial ins(9;22) followed by a reciprocal translocation between 9q34 and 22p11 would also require 5 breaks and therefore cannot be ruled out. Finally, patient no 6 had a three way cryptic t(9;22;16)(q34;q11;q?13) with 9q34 sequences embedded within the der(22), suggesting an initial ins(22;9) followed by a translocation between chromosomes 16 and der(22)ins(22;9). These data show not only that the two mechanisms do happen, but also that they are not excluding options. An example of the latter is patient no 6, where an initial direct ins(22;9) would be part of the spectrum of rearrangements that had restored the normal morphology of the der(22).
In summary, we found that the BCR/ABL1 fusion resulted from relocation of not only the 3' ABL1 sequences within BCR at 22q11.2 or 5' BCR sequences within ABL but also a considerable amount of flanking material, with distal recurrent breakpoints of the excised 3' ABL1 sequences at RAPGEF1 and RXRA regions. BCR/ABL1 resulted from a direct insertion (one step mechanism) in 6 patients and CML-T1, while in 3 patients the fusion gene was a result of a sequence of events (multiple steps). Finally, the presence of different rearrangements of both 9q34 and 22q11 regions demonstrates the genetic heterogeneity of this subgroup of CML. Future studies should be performed to confirm the presence of true breakpoint hot spots and assess their implications in Ph negative BCR/ABL1 positive CML.
AV was supported by a grant from the Anthony Nolan Trust. This work was also supported by a Leukaemia Research Fund grant (No. 05098, Jean Coubrough Charitable Trust Project).
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