Multiple copies of BCR-ABL fusion gene on two isodicentric Philadelphia chromosomes in an imatinib mesylate‑resistant chronic myeloid leukemia patient

Al-Achkar,Walid; Wafa,Abdulsamad; Moassass,Faten; Klein,Elisabeth; Liehr,Thomas

doi:10.3892/ol.2013.1225

Multiple copies of BCR-ABL fusion gene on two isodicentric Philadelphia chromosomes in an imatinib mesylate‑resistant chronic myeloid leukemia patient

Authors:
- Walid Al-Achkar
- Abdulsamad Wafa
- Faten Moassass
- Elisabeth Klein
- Thomas Liehr
View Affiliations

Affiliations: Department of Molecular Biology and Biotechnology, Human Genetics Division, Atomic Energy Commission, Damascus, Syria, Jena University Hospital, Friedrich Schiller University, Institute of Human Genetics, D-07743 Jena, Germany
Published online on: March 5, 2013 https://doi.org/10.3892/ol.2013.1225
Pages: 1579-1582

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The so-called Philadelphia (Ph) chromosome is present in more than 90% of chronic myeloid leukemia (CML) cases. Amplification or duplication of the BCR-ABL gene has been found to be one of the key factors leading to drug resistance to imatinib mesylate (IM). In the present study, we identified the presence of isodicentric Ph chromosomes [idic(Ph)] in an IM-resistant patient. Fluorescence in situ hybridization (FISH) analysis on metaphase chromosomes confirmed the heterogeneity and amplification of the fused BCR-ABL gene. FISH analysis superimposed on G-banding confirmed the presence of idic(Ph) chromosomes. Reverse transcription-polymerase chain reaction (RT-PCR) products revealed the presence of the BCR-ABL fusion transcript b3a2. The idic(Ph) chromosomes in CML were shown to be fused at the satellite regions of the short arms. The patient did not respond to IM chemotherapy and did not achieve remission. In this study, the impact of the idic(Ph) chromosomes on genomic instability, heterogeneity and amplification of the BCR-ABL gene in IM-resistant patients is discussed.

View Figures

View References

1	O’Brien S, Thall PF and Siciliano MJ: Cytogenetics of chronic myelogeneous leukaemia. Baillieres Clin Hematol. 10:259–276. 1997.
2	Shtivelman E, Lifshitz B, Gale RP and Canaani E: Fused transcript of abl and bcr genes in chronic myelogenous leukemia. Nature. 315:550–554. 1985. View Article : Google Scholar : PubMed/NCBI
3	Anastasi J, Feng J, Le Beau MM, Larson RA, Rowley JD and Vardiman JW: The relationship between secondary chromosomal abnormalities and blast transformation in chronic myelogenous leukemia. Leukemia. 9:628–633. 1995.PubMed/NCBI
4	Whang-Peng J, Knutsen TA and Lee EC: Dicentric Ph1 chromosome. J Natl Cancer Inst. 51:2009–2012. 1973.
5	Becher R, Ohl S, Schaefer UW, Wendehorst E, Quiskamp F, Mahmoud HK, Schüning F and Schmidt CG: Clonal evolution with isodicentric Ph1 chromosome in Ph1-positive CML: karyotypic conversion after bone marrow transplantation. Blut. 48:247–250. 1984. View Article : Google Scholar : PubMed/NCBI
6	Kovacs G, Georgii A and Mainzer K: Three isodicentric Philadelphia chromosomes in acute phase of chronic myeloid leukemia: a case report. Cancer Genet Cytogenet. 20:29–33. 1986. View Article : Google Scholar : PubMed/NCBI
7	Pernice F, Squadrito G, Saitta A, Mazza G and Musolino C: Isodicentric Philadelphia chromosome in accelerated phase of chronic myeloid leukemia. Cancer Genet Cytogenet. 66:113–116. 1993. View Article : Google Scholar : PubMed/NCBI
8	Szych CM, Liesveld JL, Iqbal MA, Li L, Siebert S, Asmus C, O’Malley J, Lee A and Wang N: Isodicentric Philadelphia chromosomes in imatinib mesylate (Gleevec)-resistant patients. Cancer Genet Cytogenet. 174:132–137. 2007. View Article : Google Scholar : PubMed/NCBI
9	Li Ming Chua C, Tan YY, Chua SP, Ma HB, Koay E, Li Min Poon M, Liu TC and Gole L: Multiple copies of a rare rearrangement of Philadelphia chromosome in a chronic myeloid leukemia patient: a case report. Cancer Genet Cytogenet. 199:66–68. 2010.PubMed/NCBI
10	Yamamoto K, Nagata K, Morita Y, Inagaki K and Hamaguchi H: Isodicentric Philadelphia chromosome in acute lymphoblastic leukemia with der(7;12)(q10;q10). Leuk Res. 31:713–718. 2007. View Article : Google Scholar : PubMed/NCBI
11	Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R and Scapozza L: Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. Lancet Oncol. 4:75–85. 2003. View Article : Google Scholar : PubMed/NCBI
12	O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R and Druker BJ; IRIS Investigators: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 348:994–1004. 2003.
13	Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Resta D, Capdeville R, Zoellner U, Talpaz M and Druker B: Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 346:645–652. 2002. View Article : Google Scholar : PubMed/NCBI
14	Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F, Schiffer CA, Fischer T, Deininger MWN, Lennard AL, et al: Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic phase chronic myeloid leukemia: results of a phase 2 study. Blood. 99:1928–1937. 2002. View Article : Google Scholar : PubMed/NCBI
15	Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG, Schiffer CA, Talpaz M, Guilhot F, Deininger MWN, et al: Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 99:3530–3539. 2002. View Article : Google Scholar : PubMed/NCBI
16	Hochhaus A, Kreil S, Corbin AS, La Rosée P, Müller MC, Lahaye T, Hanfstein B, Schoch C, Cross NCP, Berger U, Gschaidmeier H, Druker BJ and Hehlmann R: Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 16:2190–2196. 2002. View Article : Google Scholar : PubMed/NCBI
17	Al-Achkar W, Wafa A and Nweder MS: A complex translocation t(5;9;22) in Philadelphia cells involving the short arm of chromosome 5 in a case of chronic myelogenous leukemia. J Exp Clin Cancer Res. 26:411–415. 2007.PubMed/NCBI
18	Shaffer L, Slovak M and Campbell L: ISCN (2009): An International System for Human Cytogenetic Nomenclature. S. Karger; Basel: 2009
19	Trifonov V, Seidel J, Starke H, Martina P, Beensen V, Ziegler M, Hartmann I, Heller A, Nietzel A, Claussen U and Liehr T: Enlarged chromosome 13 p-arm hiding a cryptic partial trisomy 6p22.2-pter. Prenat Diagn. 23:427–430. 2003. View Article : Google Scholar : PubMed/NCBI
20	Ewers E, Yoda K, Hamid AB, Weise A, Manvelyan M and Liehr T: Entromere activity in dicentric small supernumerary marker chromosomes. Chromosome Res. 18:555–562. 2010. View Article : Google Scholar : PubMed/NCBI
21	Al-Achkar W, Wafa A, Ali BY, Manvelyan M and Liehr T: A rare chronic myeloid leukemia case with Philadelphia chromosome, BCR-ABL e13a3 transcript and complex translocation involving four different chromosomes. Oncol Lett. 1:797–800. 2010.PubMed/NCBI
22	Barnes DJ, Palaiologou D, Panousopoulou E, Schultheis B, Yong AS, Wong A, Pattacini L, Goldman JM and Melo JV: Bcr-Abl expression levels determine the rate of development of resistance to imatinib mesylate in chronic myeloid leukemia. Cancer Res. 65:8912–8919. 2005. View Article : Google Scholar : PubMed/NCBI
23	Le Coutre P, Tassi E, Varella-Garcia M, Barni R, Mologni L, Cabrita G, Marchesi E, Supino R and Gambacorti-Passerini C: Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood. 95:1758–1766. 2000.PubMed/NCBI
24	Campbell LJ, Patsouris C, Rayeroux KC, Somana K, Januszewicz EH and Szer J: BCR/ABL amplification in chronic myelocytic leukemia blast crisis following imatinib mesylate administration. Cancer Genet Cytogent. 139:30–33. 2002. View Article : Google Scholar : PubMed/NCBI