- Case report
- Open Access
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
© Yokota et al.; licensee BioMed Central Ltd. 2012
- Received: 19 December 2011
- Accepted: 1 May 2012
- Published: 1 May 2012
About 5-10 % of chronic myelogenous leukemia (CML) patients show variant Philadelphia (Ph) translocations. The formation mechanisms and clinical significance of variant Ph translocations remain unclear. We report a CML case with a novel five-way complex translocation. Although the result of initial G-banding was 46,XY,t(7;11;9)(q22;q13;q34),t(9;22)(q34;q11.2), fluorescence in situ hybridization (FISH) demonstrated t(7;11;9;22;9)(q22;q13;q34;q11.2;q34) consisting of sequential rearrangements involving five chromosomes. The patient was successfully treated by imatinib and obtained a major molecular response. To our knowledge, this is the tenth CML case with a complicated Ph translocation involving five chromosomes and the third one treated by imatinib. Good response with imatinib therapy suggested that a single-event rearrangement was involved in the chromosomal changes.
- Variant Ph translocation
- Five-way translocation
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder of primitive hematopoietic stem cells. Most CML patients show a Philadelphia (Ph) chromosome with the characteristic t(9;22)(q34;q11.2) translocation. However, about 5-10 % of Ph positive patients with CML show variant translocations. The formation mechanisms and clinical significance of variant Ph translocations remain unclear.
We describe a CML case with a novel five-way chromosomal translocation t(7;11;9;22;9)(q22;q13;q34;q11.2;q34), who has been successfully treated by imatinib. To our knowledge, this is the tenth CML case with a complicated Ph translocation involving five chromosomes, and the third one treated by imatinib.
The patient was 58-year-old Japanese male with no significant medical history. He was found to have increased white blood cell count (WBC) at a medical checkup at his workplace and referred to our hospital. The laboratory data on admission showed that his WBC was 19.1 × 109/L, with a differential of 67.5 % neutrophils, 5.5 % myelocytes, 3.0 % metamyelocytes, 6.0 % basophils, 1.5 % eosinophils, 3.0 % monocytes, 13.5 % lymphocytes. Hemoglobin concentration of 13.0 g/dL was within a normal range and platelet count of 390 × 109/L was slightly elevated. Neutrophil alkaline phosphatase (NAP) score was decreased to 79 (control score, 170–285). Bone marrow aspirate showed marked hypercellularity. Reverse-transcription polymerase chain reaction (RT-PCR) of RNA from his bone marrow cells amplified major BCR/ABL chimeric transcript (b3a2 type). He was diagnosed as having CML in the chronic phase, then received treatment with orally imatinib at daily of 400 mg. He obtained a complete cytogenetic response as well as a major molecular response (MMR), as BCR/ABL transcripts have not been detected by quantitative RT-PCR analysis after thirteen months treatment. The MMR status has been maintained for 44 months.
To confirm these cytogenetic aberrations, we performed Spectral karyotyping (SKY) analysis with a SkyPaint kit (Applied Spectral Imaging, Migdal Ha’Emek, Israel). As shown in Figure 1B, SKY confirmed four derivative chromosomes, der(9)t(9;11)(q34;q13), der(9)t(9;22)(q34;q11), der(11)t(7;11)(q22;q13), and der(22)t(9;22)(q34;q11). SKY could not visualize the small segment 9q34-9qter on the der(7)t(7;9)(q22;q34). The size of this segment was supposed to be smaller than a minimum genomic alteration that SKY could detect.
Additionally, we used two types of probe. One is the CEP7 (Vysis, Inc.) (Spectrum Green) that hybridizes to the centromere of chromosome 7 (assay 2). The other is the mixture consisted of 11p (Spectrum Green), 11q (Spectrum Orange), 18p (Spectrum Green and Spectrum Orange) and 18 centromeric (Spectrum Aqua) probes (Vysis, Inc. ) (assay 3). Assay 2 indicate that the ASS-ABL segment (larger red signal) from the chromosome 9 was on der(7) with CEP7 signal. The fusion BCR/ABL signal was on der(22), and the smaller red signal, ASS, was retained on the other chromosome 9 (Figure 2B). In assay 3, the larger red signal, 11q, was on one of der(9) which retained the smaller red signal ASS (Figure 2C), indicating that the 11q segment was translocated to a chromosome 9 with rearrangement within the ABL, but not to the other from which ASS-ABL was translocated to der(7).
Previously reported CML cases with five-way translocations and the present case
Karyotype of five-way translocation
Died in benign phase
BSF/VCR and PSL/ADM, CPA and MTX
Died 33 months
DNR,VCR,AND and PSL
Died 34 months
The present case
Two possible mechanisms have been postulated for formation of variant translocations. One is a single-event rearrangement via 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 translocation events involving chromosomes 9 and 22 and other chromosomes . These mechanisms may have prognostic importance in that a single genomic rearrangement may confer a similar prognosis to the classical Ph translocation, whereas a multi-step mechanism represents clonal evolutions associated with a worse prognosis .
Conflicting data were reported on clinical relevance of variant Ph translocation to tyrosine kinase inhibitor treatment [14–16] and its clinical significance has not been determined yet. Our case had achieved a MMR by imatinib therapy, suggesting that a single-event rearrangement was involved in the chromosomal change. However, careful follow-up will be needed, as complex translocations might be associated with a higher degree of genomic instability.
We report a patient with CML presenting a complex five-way translocation, t(7;11;9;22;9)(q22;q13;q34;q11.2;q34). In our case, the initial finding on G-banding analysis suggested that an additional chromosomal aberration would occur independently from the Ph translocation. Chromosomal breaks occurred on both alleles of band 9q34 in the translocation, but only one of them was involved for the formation of BCR/ABL fusion. FISH method identified sequential rearrangements involving five chromosomes. Good response with imatinib therapy suggested that a single-event rearrangement was involved in the chromosomal changes.
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this Journal.
We would like to thank Dr. Ikuo Miura and Dr. Masako Minamihisamatsu for reading the manuscript and useful suggestion.
- Nakajima F, Takagi M, Tsuchiya K, Imashuku S, Arakawa S, Misawa S, Abe T: A five-way complex translocation in a patient with chronic myelocytic leukemia: t(4;18;13;9;22)(q12;q11.2;q14;q34;q11.2). Cancer Genet Cytogenet 1988, 30: 163–164. 10.1016/0165-4608(88)90106-9View ArticlePubMedGoogle Scholar
- Hayata I, Sasaki M: A case of Ph1-positive chronic myelocytic leukemia associated with complex translocation. Proc Japan Acad 1976, 52: 29–32.Google Scholar
- Potter AM, Watmore AE, Cooke P, Lilleyman JS, Sokol RJ: Significance of non-standard Philadelphia chromosomes in chronic granulocytic leukaemia. Br J Cancer 1981, 44: 51–54. 10.1038/bjc.1981.146PubMed CentralView ArticlePubMedGoogle Scholar
- Abe R, Shiga Y, Ookoshi T, Tanaka T, Maruyama Y: A complicated translocation involving five chromosomes (Nos. 9, 11, 12, 21 and 22) in a patient with chronic myelocytic leukemia (CML). Int J Hematol 1991, 54: 479–482.PubMedGoogle Scholar
- Lau LC, Knight L, Tien SL, Lim P, Yong MH, Chong YY: Highly complex chromosomal rearrangement of chromosome 9 in a case of chronic myeloid leukemia. Cancer Genet Cytogenet 1998, 104: 153–156. 10.1016/S0165-4608(97)00451-2View ArticlePubMedGoogle Scholar
- Young C, Di Benedetto J, Glasser L, Mark HFL: A Philadelphia chromosome positive CML patient with a unique translocation studied via GTG-banding and fluorescence in situ hybridization. Cancer Genet Cytogenet 1996, 89: 157–162. 10.1016/0165-4608(96)00029-5View ArticlePubMedGoogle Scholar
- Morel F, Herry A, Le Bris MJ, Morice P, Bouquard P, Abgrall JF, Berthou C, De Braekeleer M: Contribution of fluorescence in situ hybridization analyses to the characterization of masked and complex Philadelphia chromosome translocations in chronic myelocytic leukemia. Cancer Genet Cytogenet 2003, 147: 115–120. 10.1016/S0165-4608(03)00204-8View ArticlePubMedGoogle Scholar
- Ikuta K, Torimoto Y, Jimbo J, Inamura J, Hosoki T, Shindo M, Sato K, Takahashi H, Kohgo Y: A novel five-way chromosomal translocation observed in chronic myelogenous leukemia. Cancer Genet Cytogenet 2008, 183: 69–71. 10.1016/j.cancergencyto.2008.02.002View ArticlePubMedGoogle Scholar
- Al Achkar W, Wafa A, Mkrtchyan H, Moassass F, Liehr T: Novel complex translocation involving 5 different chromosomes in a chronic myeloid leukemia with Philadelphia chromosome: a case report. Mol Cytogenet 2009, 2: 21–24. 10.1186/1755-8166-2-21PubMed CentralView ArticlePubMedGoogle Scholar
- Mitelman F, Johansson B, Mertens F: Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer (2010).1991. [http://cgap.nci.nih.gov/Chromosomes/Mitelman]Google Scholar
- Fitzgerald PH, Morris CM: Complex chromosomal translocations in the Philadelphia chromosome leukemia. Serial translocations or a concerted genomic rearrangement? Cancer Genet Cytogenet 1991, 57: 143–157. 10.1016/0165-4608(91)90145-KView ArticlePubMedGoogle Scholar
- Nacheva E, Holloway T, Brown K, Bloxham D, Green AR: Philadelphia-negative chronic myeloid leukaemia: detection by FISH of BCR-ABL fusion gene localized either to chromosome 9 or chromosome 22. Br J Haematol 1994, 87: 409–412. 10.1111/j.1365-2141.1994.tb04933.xView ArticlePubMedGoogle Scholar
- Reid AG, Huntly BJP, Grace C, Green AR, Nacheva EP: Survival implication of molecular heterogeneity in variant Philadelphia-positive chronic myeloid leukaemia. Br J Haematol 2003, 121: 419–427. 10.1046/j.1365-2141.2003.04291.xView ArticlePubMedGoogle Scholar
- El-Zimaity MM, Kantarjian H, Talpaz M, O’Brien S, Giles F, Garcia-Manero G, Verstovsek S, Thomas D, Ferrajoli A, Hayes K, Bekele N, Zhou X, Rios MB, Glassman AB, Cortes JE: Results of imatinib mesylate therapy in chronic myelogenous leukaemia with variant Philadelphia chromosome. Br J Haematol 2004, 125: 187–195. 10.1111/j.1365-2141.2004.04899.xView ArticlePubMedGoogle Scholar
- Stagno F, Vigneri P, Del Fabro V, Stella S, Cupri A, Massimino M, Consoli C, Tambe L, Consoli ML, Antolino A, Di Raimondo F: Influence of complex variant chromosomal translocations in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Acta Oncol 2010, 49: 506–508. 10.3109/02841861003660031View ArticlePubMedGoogle Scholar
- Marin D, Milojkovic D, Olavarria E, Khorashad JS, de Lavallade H, Reid AG, Foroni L, Rezvani K, Bua M, Dazzi F, Pavlu J, Klammer M, Kaeda JS, Goldman JM, Apperley JF: European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood 2008, 112: 4437–4444. 10.1182/blood-2008-06-162388View ArticlePubMedGoogle Scholar
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