Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
Year : 2015  |  Volume : 11  |  Issue : 3  |  Page : 654

Variant Philadelphia translocations in chronic myeloid leukemia: A report of five cases

1 Department of Pathology, MS Ramaiah Medical College and Hospital, Bangalore, Karnataka, India
2 Department of Medical Oncology, MS Ramaiah Medical College and Hospital, Bangalore, Karnataka, India
3 Department of Cytogenetics, MS Ramaiah Medical College and Hospital, Bangalore, Karnataka, India

Date of Web Publication9-Oct-2015

Correspondence Address:
Vijaya V Mysorekar
89, AG's Office Colony, 5th Main, 6th Cross, New BEL Road, Bangalore - 560 054, Karnataka
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.138036

Rights and Permissions
 > Abstract 

The t (9;22)(q34;q11) translocation is found in about 90% of the chronic myeloid leukemia patients. About 5 - 10% of these patients have complex variant translocations involving a third chromosome in addition to chromosomes 9 and 22. We describe five male patients in the chronic myeloid leukemia-chronic phase, with rare variant Philadelphia translocations. All of them had the BCR-ABL fusion gene and responded well to treatment with imatinib mesylate. All the patients are on regular follow-up.

Keywords: BCR-ABL fusion gene, chronic myeloid leukemia, fluorescence in situ hybridization, variant Philadelphia translocation

How to cite this article:
Mysorekar VV, Subramanian M, Kilara N, Sundareshan TS. Variant Philadelphia translocations in chronic myeloid leukemia: A report of five cases. J Can Res Ther 2015;11:654

How to cite this URL:
Mysorekar VV, Subramanian M, Kilara N, Sundareshan TS. Variant Philadelphia translocations in chronic myeloid leukemia: A report of five cases. J Can Res Ther [serial online] 2015 [cited 2018 Dec 12];11:654. Available from: http://www.cancerjournal.net/text.asp?2015/11/3/654/138036

 > Introduction Top

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of the Philadelphia (Ph) chromosome, resulting from a balanced reciprocal translocation between the long arms of chromosome 9 and 22, t (9;22)(q34;q11). [1] In the formation of the Ph chromosome, the 3′ region of the ABL oncogene is transposed from 9q34 to the 5′ region of the BCR gene on chromosome 22 to form a fusion gene BCR-ABL, which encodes a constitutively active protein, tyrosine kinase. [2] Although a vast majority of patients with CML show the classical t (9;22)(q34;q11) translocation, in 5-10% of the cases, variant Ph translocations are observed. These are cytogenetically classified as simple variant translocations involving chromosome 22 and a chromosome other than 9, and complex variants that involve chromosomes 9, 22, and one or more other chromosomes in addition to 9 and 22. [2] Occasionally, the chromosomal changes are submicroscopic and the masked Ph translocation or other cryptic abnormalities can be revealed only by fluorescence in situ hybridization (FISH) or by molecular analysis. [3]

We describe five cases of CML having rare/unique variant and complex Philadelphia translocations. These constitute 8.9% of the total of 56 Ph-positive CML patients encountered in our laboratory.

 > Case reports Top

All the five patients with variant Ph translocations were males, and their age ranged from 21 to 90 years. The clinical details and cytogenetic results of the five cases are summarized in [Table 1]. Their peripheral blood picture and bone marrow findings were consistent with the diagnosis of the chronic phase of CML [Figure 1]. Conventional cytogenetic analysis was performed on unstimulated 24-hour cultures of bone marrow aspirates, after staining with trypsin-Giemsa (GTG-banding). A minimum of 20 metaphases were analyzed in each case. The partial karyotypes of the five cases are shown in [Figure 2]. In case 5, FISH was performed on interphase nuclei and metaphases, using the dual color, dual fusion probe, XL BCR/ABL1 Plus from MetaSystems, GmbH, Germany. It revealed a BCR-ABL fusion gene on chromosome 22q, from a cryptic translocation t (9;14;22), which was not evident on conventional karyotyping [Figure 3]. In all the five cases, BCR-ABL was positive by real-time, reverse transcriptase polymerase chain reaction (RT-PCR) assay. All the patients showed a good response to treatment with imatinib mesylate, a tyrosine kinase inhibitor, and are on regular follow-up.
Figure 1: (a) Peripheral smear (Case 5) showing immature myeloid cells, and basophils (Leishman's stain, x1000). (b) Bone marrow trephine biopsy (Case 5) showing granulocytic hyperplasia (Hematoxylin and Eosin, x200)

Click here to view
Figure 2: Partial karyotypes of the five cases. Case 1: 46,XY,t(16;22) (q24;q11), Case 2: 46,XY,t(15;22)(p11;q11), Case 3: 46,XY,t(1;9;22) (q23;q34;q11), Case 4: 46,XY,t(9;9;22)(p11;q34;q11), and Case 5: 46,XY,t(9;14;22)(q34;q32;q11); however, note that in case 5, chromosome 9 does not show any obvious abnormality. (G-banding: Giemsa stain-enzyme trypsin, x1000)

Click here to view
Figure 3: FISH in Case 5, in (a) interphase nuclei and (b) metaphase spreads, showing two ABL signals on chromosome 9 (red), two BCR signals (green), one on the normal chromosome 22 and the other on chromosome 14, and the fusion gene BCR-ABL (yellow) on 22q

Click here to view
Table 1: Clinical details and cytogenetic results of the five cases

Click here to view

 > Discussion Top

Any chromosome can be the third chromosome involved in variant rearrangements in CML. The distribution of the breakpoints has been found to be preferentially in the cytosine-guanine (CG)-rich regions, that is, light regions of the chromosome. [4] It has been suggested that the distribution of the breakpoints is non-random with the chromosomal bands most susceptible to breakage being: 1p36, 3p21, 5q31, 6p21, 9q22, 10q22, 11q13, 12p13, 17p13, 17q21, 17q25, 19q13, 21q22, 22q12, and 22q13. [5] However, the location of the BCR-ABL fusion gene remains on the long arm of chromosome 22 (22q) in most cases. [2],[3],[5] In our cases, the breakpoints were situated at less common sites, namely, 16q24, 15p11, 1q23, 9p11, and 14q32, and the BCR-ABL was positive in all the cases. Al-Achkar et al. [2] described a case of t (9;22;21)(q34;q11;p12) with a BCR/ABL fusion residing on the der (22) and the 3'BCR region translocated on the short arm of derivative chromosome 21. The patient was successfully treated with imatinib. Manabe et al. [6] described the case of a male with CML-chronic phase showing a complex translocation, t (9;22;16)(q34;q11;q24). Subsequently, an additional chromosomal abnormality, trisomy 8 appeared, but a major molecular response was obtained after one year of imatinib mesylate therapy. Yokota et al. [7] reported a CML case with a novel five-way complex translocation, karyotype, 46,XY,t(7;11;9;22;9)(q22;q13;q34;q11.2;q34). The fusion BCR/ABL signal was on der (22). The patient was successfully treated with imatinib. In the case described by Cianciulli et al., [8] the BCR-ABL fusion gene was located on the short arm of der (9) (9p), the karyotype being 46,XX,t(9;9;22)(p13;q34;q11). This patient also showed a good hematological and cytogenetic response following imatinib therapy. Marzocchi et al. [3] discussed 30 CML cases with variant translocations, involving three or four chromosomes. In addition to chromosomes 9 and 22, the most involved chromosomes were 17, 1, 9, 11, 12, and 15. Only one case carried an additional cytogenetic abnormality: t (7;19)(q21;p13). In all, except two of their cases, the BCR-ABL fusion gene was located on der (22q). Deletions of der (9q) were present in six cases (20%). The presence of variant translocations did not influence the response to imatinib therapy, in their experience.

Two likely mechanisms have been postulated for the occurrence of complex variant translocations, as in our cases 3, 4, and 5. One is a single-step rearrangement, where there is simultaneous breakage of several chromosomes followed by mismatched joining. The other is a multi-step mechanism in which a classical Ph translocation is followed by further translocations involving chromosomes 9 and 22 and other chromosomes. These mechanisms may have prognostic importance, in that, a single-step rearrangement may confer a prognosis similar to the classical Ph translocation, whereas, a multi-step mechanism represents clonal evolutions carrying a worse prognosis. [7] Regarding cases 1 and 2, where apparently only chromosome 16 or 15, respectively, was involved in the translocation along with chromosome 22, we can suggest two possibilities: (1) ABL might have been aberrantly situated on chromosome 16/15 instead of 9q34. (2) These might indeed have been cryptic translocations t (9;16;22) and t (9;15;22), which were beyond the resolution of conventional karyotyping. The limitation here is that FISH was not done for these patients on account of their poor economic status.

As already stated, the prognosis of CML in the chronic phase with variant translocations has been found to be similar to that of CML with the classical Ph translocation, in most studies. [2],[3],[6],[7],[8] Our patients also responded well to treatment with imatinib. On the other hand, some reports state that patients harboring complex variant translocations at diagnosis, show a poor clinical outcome due to their relative genomic instability in comparison to patients with classical t (9;22) without variant translocations. [9] Deletions on der (9) flanking the t (9;22) breakpoint, have been observed more frequently in variant translocations. [3],[4] These deletions are submicroscopic and can be detected by FISH or polymerase chain reaction (PCR). They are thought to occur at the time of the Ph translocation and are associated with worse survival. [10]

 > Conclusion Top

Variant Philadelphia translocations can occur in chronic myeloid leukemia. All our five patients with variant Philadelphia translocations have so far responded well to treatment with tyrosine kinase inhibitors. However, they need a prolonged follow-up.

 > References Top

Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973;243:290-3.  Back to cited text no. 1
Al-Achkar W, Wafa A, Moassass F, Liehr T. A chronic myeloid leukemia case with a unique variant Philadelphia translocation: t (9;22;21)(q34;q11;p12). Oncol Lett 2012;3:1027-9.  Back to cited text no. 2
Marzocchi G, Castagnetti F, Luatti S, Baldazzi C, Stacchini M, Gugliotta G, et al. Variant Philadelphia translocations: Molecular-cytogenetic characterization and prognostic influence on frontline imatinib therapy, a GIMEMA Working Party on CML analysis. Blood 2011;117:6793-800.  Back to cited text no. 3
Bennour A, Sennana H, Laatiri MA, Elloumi M, Khelif A, Saad A. Molecular cytogenetic characterization of variant Philadelphia translocations in chronic myeloid leukemia: Genesis and deletion of derivative chromosome 9. Cancer Genet Cytogenet 2009;194:30-7.  Back to cited text no. 4
Johansson B, Fioretos T, Mitelman F. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol 2002;107:76-94.  Back to cited text no. 5
Manabe M, Yoshii Y, Mukai S, Sakamoto E, Kanashima H, Inoue T, et al. A rare t (9;22;16)(q34;q11;q24) translocation in chronic myeloid leukemia for which imatinib mesylate was effective: A case report. Leuk Res Treatment 2011;2011:592519.  Back to cited text no. 6
Yokota S, Nakamura Y, Bessho M. A novel five-way translocation t (7;11;9;22;9)(q22;q13;q34;q11.2;q34) involving Ph chromosome in a patient of chronic myeloid leukemia: A case report. Mol Cytogenet 2012;5:20.  Back to cited text no. 7
Cianciulli AM, Marzano R, Merola R, Orlandi G, Petti MC, Guadagni F, et al. Complex variant Philadelphia translocation involving the short arm of chromosome 9 in a case of chronic myeloid leukemia. Haematologica 2004;89:ECR37.  Back to cited text no. 8
Stagno F, Vigneri P, Del Fabro V, Stella S, Cupri A, Massimino M, et al. Influence of complex variant chromosomal translocations in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Acta Oncol 2010;49:506-8.  Back to cited text no. 9
Gorusu M, Benn P, Li Z, Fang M. On the genesis and prognosis of variant translocations in chronic myeloid leukemia. Cancer Genet Cytogenet 2007;173:97-106.  Back to cited text no. 10


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Case reports>Discussion>Conclusion>Article Figures>Article Tables
  In this article

 Article Access Statistics
    PDF Downloaded228    
    Comments [Add]    

Recommend this journal