Skip to main content
Download PDF

A unique three-way Philadelphia chromosome variant t(4;9;22)(q21;q34;q11.2) in a newly diagnosed patient with chronic phase chronic myeloid leukemia: a case report and review of the literature

Journal of Medical Case Reports volume 15, Article number: 285 (2021) Cite this article

Abstract

Background

Chronic myeloid leukemia is a hematologic malignancy associated with the fusion of two genes: BCR and ABL1. This fusion results from a translocation between chromosomes 9 and 22, which is called the Philadelphia chromosome. Although the Philadelphia chromosome is present in more than 90% of patients with chronic myeloid leukemia, 5–8% of patients with chronic myeloid leukemia show complex variant translocations. Herein, we report a unique case of a three-way translocation variant in chronic phase chronic myeloid leukemia.

Case presentation

A 40-year-old Asian male who presented with leukocytosis was diagnosed with chronic phase chronic myeloid leukemia. Cytogenetic karyotyping analysis showed 46,XY,t(4;9;22)(q21;q34;q11.2). He was treated with bosutinib and then changed to dasatinib because of intolerance, and MR4.5 (BCR-ABL/ABL ≦ 0.0032%, international scale) was achieved after 17 months of continuous treatment.

Conclusion

This was the 14th case of t(4;9;22), in particular, a new variant Ph translocation involved in chromosome 4q21 and the first successful case treated with tyrosine kinase inhibitors in the world. We summarize previous case reports regarding three-way variant chromosome translocation, t(4;9;22) and discuss how this rare translocation is linked to prognosis.

Peer Review reports

Introduction

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the dysregulated production and uncontrolled proliferation of mature granulocytes with normal differentiation. CML is associated with the BCR-ABL1 fusion gene that results from a translocation between chromosomes 9 and 22, t(9;22)(q34;q11), called the Philadelphia (Ph) chromosome [1]. BCR-ABL1 is capable of autophosphorylation and uncontrolled signaling to multiple downstream oncogenic proteins in CML [2]. Tyrosine kinase inhibitors (TKIs) inhibit the initiation of the BCR-ABL1 pathway and are effective, frontline therapies for chronic phase (CP) CML (CML-CP) [3].

Ph chromosome is present in more than 90% of CML patients, and only about 5% of CML patients show complex variant translocations, which is due to the participation of one or more chromosomes other than 9 and 22 [4]. The mechanisms of the generation of the variant translocations are not fully understood. While some previous studies have suggested that CML patients with variant Ph translocations may have a worse outcome than those with classic translocations, other studies have shown that patients with variant Ph translocations have an outcome similar to those with classic Ph translocations when treated with imatinib mesylate [4, 5].

Herein, we describe a unique case of CML-CP with a three-way Ph chromosome variant t(4;9;22)(q21;q34;q11.2). This was the 14th case of t(4;9;22), in particular, a new variant Ph translocation involved in chromosome 4q21 and the first case treated with TKIs. In addition, we summarize previous case reports regarding three-way variant chromosome translocation t(4;9;22) and discuss how this rare translocation is linked to pathogenesis, disease characteristics, treatment responses, and prognosis.

Case presentation

A 40-year-old Asian male with leukocytosis visited our hospital in June 2017. His physical examination was unremarkable, and no hepatosplenomegaly was observed. Hematological analysis revealed a white blood cell (WBC) count of 89.34 × 109/l, consisting of 67.0% neutrophils, 5.5% lymphocytes, 0.5% monocytes, 0.5% eosinophils, 3.0% basophils, 1.5% promyelocytes, 14.5% myelocytes, and 7.5% metamyelocytes, a hemoglobin level of 12.6 g/dl, and platelet count of 381 × 109/l. The bone marrow aspirate showed hypercellular bone marrow with 10.2% erythroid precursors, 0.2% myeloid blasts, 4.8% promyelocytes, 23.0% myelocytes, 17.0% metamyelocytes, 33.0% neutrophils, 8.2% eosinophils, 1.4% basophils, 1.8% lymphocytes, and 0.4% monocytes. Cytogenetic analysis was performed utilizing bone marrow culture cells, and all analyzed cells showed a complex, three-way (4;9;22)(q21;q34;q11.2) Ph chromosome translocation (Fig. 1). Therefore, he was diagnosed with CML-CP, and his Sokal and EUTOS long-term survival (ELTS) score were 0.586 (low risk) and 0.8248 (low risk), respectively.

Fig. 1
figure 1

Cytogenetic analysis showing a variant three-way translocation: 46, XY, t(4;9;22)(q21;q34;q11.2). Arrowheads indicate all the derivative chromosomes

Full size image

Initially, he was treated with orally administered bosutinib at a daily dose of 400 mg. However, he had transient, grade 3 or 4 elevations in liver transaminases during treatment. Therefore, bosutinib was discontinued, and dasatinib at a daily dose of 100 mg was administered in December 2017. His BCR-ABL/ABL levels at 3, 6, and 12 months were 2.4188%, 2.7149%, and 0.0062%, respectively. Seventeen months after initial treatment, MR4.5 [BCR-ABL/ABL ≦ 0.0032% international scale (IS)] was achieved, and complete molecular response (CMR) was confirmed in April 2019 (Fig 2).

Fig. 2
figure 2

Clinical course in a 40-year-old man patient with CML-CP

Full size image

Literature review and discussion

Ph chromosome is present in more than 90% of CML patients, and only about 5–8% of CML patients show complex variant translocations due to the participation of one or more chromosomes other than chromosomes 9 and 22 [4,5,6,7]. Fabarius et al. analyzed 1151 patients with Ph-chromosome-positive CML, and 69 patients (6.0%) had variant Ph translocations. Fifty two patients had three-way variant Ph translocation, and the frequency of the third partner chromosome for the three-way Ph variant translocation was 6/52 for chromosome 2 and 6/52 for chromosome 15. Only 2 patients in these 52 patients with three-way variant Ph translocation had t(4:9:22) [6].

On literature review, we found that t(4;9;22) as complex variant translocations has been reported in only 13 cases of CML [6, 8,9,10,11,12,13,14,15]. Table 1 presents a summary. In these cases, 4p16 and 4q25 have been reported as the major breakpoints on chromosome 4. However, the breakpoint at 4q21 is novel. Potentially relevant genes located on chromosome 4q21 are protein tyrosine-phosphatase non-receptor type 13 (PTPN13) [16], chemokine (C-X-C motif) ligand (CXCL)9–11 [17], RAP1 GTPase-GDP dissociation stimulator 1 (RAP1GDS1) [18], and ALL1-fused gene from chromosome 4.

Table 1. Summary of CML patients with t(4;9;22) in previous reports
Full size table

AF4)[19] . The PTPN13 gene encodes the PTPN13, which is a negative regulator of tumor growth in human breast and ovarian cancer [20], but its pathological role in CML and tumor sensitivity in tyrosine kinase inhibitors are not known. CXCR9-11 are CXCR3/CCR5 chemokine ligands and linked to T-helper 1 responses, which are important to antitumor immunity. The tumor microenvironment of CML is immunosuppressive, as cytotoxic T-cell function is extremely suppressed [21]. AF4 encodes a serine/proline-rich protein and is involved in transcriptional activation [22]. In addition, AF4 plays an important role in oncogenesis of acute lymphoblastic leukemia because the mixed lineage leukemia (MLL) gene located on 11q23 fuses to the AF4 genes and makes a chimera MLL/AF4 fusion protein [23,24,25]. MLL/AF4 chimera contributes to enhancing the hematopoietic repopulating cell function and clonogeneic potential that plays a crucial role in leukemogenesis [26]. Interestingly, a three-way translocation involving 4q21, t(4;15;17)(q21;q22;q21) was also reported in acute promyelocytic leukemia (APL) [27]. Unfortunately, we have no available samples to test these imporant genes in this case.

Regarding the clinical characteristics of previous reports, six patients were <60 years old, and the sex ratio (male to female) was about 3:1. Unfortunately, treatment was not described in most cases, although patients with variant Ph translocations treated with imatinib mesylate had a similar prognosis to those without variant Ph translocations [4, 5]. However, trisomy 8, a second Ph chromosome, isochromosome 17q, or trisomy 19 seem to have a negative impact on survival and progression [6]. There is no evidence showing that selection of second-generation TKIs benefit these patients, but Tirrò et al. reported that second-generation TKIs may be effective in these patients [28]. Similarly, our patient was treated with a second-generation TKI that was associated with a rapid decrease in BCR-ABL/ABL transcripts and achieved MR4.5 at 17 months after initial treatment. Our case is the first successful report treated with TKIs for patients with t(4;9;22)(q21;q34;q11.2). However, because this particular translocation has not been previously described, we cannot comment on its impact on clinical course. Further studies will be required to determine the effectiveness of TKIs in CML with this particular variant translocation.

While mechanisms promoting the generation of the variant translocations observed in CML are poorly understood, two different mechanisms have been suggested. A one-step mechanism in which chromosome breakage occurs on three different chromosomes simultaneously and leads to a three-way translocation has been suggested. Others have proposed a two-step mechanism in which a standard two-way t(9;22) translocation is followed by subsequent translocations involving an additional chromosome [29, 30].

Conclusion

We report the first case of a complex three-way Ph chromosome variant t(4;9;22)(q21;q34;q11.2) successfully treated with a second-generation TKI. The pathological role of this complex three-way Ph chromosome variant warrants further study.

Availability of data and materials

All data generated or analyzed during this study are included in this published article. Additional information is available from the corresponding author upon reasonable request.

Abbreviations

CML:

Chronic myeloid leukemia

Ph:

Philadelphia

CP:

Chronic phase

TKIs:

Tyrosine kinase inhibitors

WBC:

White blood cell

CMR:

Complete molecular response

PTPN13:

Protein tyrosine-phosphatase non-receptor type 13

CXCL:

Chemokine (C-X-C motif) ligand

RAP1GDS1:

RAP1 GTPase-GDP dissociation stimulator 1

AF4:

ALL1-fused gene from chromosome 4

MLL:

Mixed lineage leukemia

References

  1. Rowley JD. Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243(5405):290–3.

    Article  CAS  Google Scholar 

  2. Apperley JF. Chronic myeloid leukaemia. Lancet. 2015;385(9976):1447–59.

    Article  Google Scholar 

  3. Rosti G, Castagnetti F, Gugliotta G, Baccarani M. Tyrosine kinase inhibitors in chronic myeloid leukaemia: which, when, for whom? Nat Rev Clin Oncol. 2017;14(3):141–54.

    Article  CAS  Google Scholar 

  4. 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(25):6793–800.

    Article  CAS  Google Scholar 

  5. El-Zimaity MM, Kantarjian H, Talpaz M, O’Brien S, Giles F, Garcia-Manero G, et al. Results of imatinib mesylate therapy in chronic myelogenous leukaemia with variant Philadelphia chromosome. Br J Haematol. 2004;125(2):187–95.

    Article  CAS  Google Scholar 

  6. Fabarius A, Leitner A, Hochhaus A, Muller MC, Hanfstein B, Haferlach C, et al. Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood. 2011;118(26):6760–8.

    Article  CAS  Google Scholar 

  7. Albano F, Specchia G, Anelli L, Zagaria A, Storlazzi CT, Buquicchio C, et al. Genomic deletions on other chromosomes involved in variant t(9;22) chronic myeloid leukemia cases. Genes Chromosom Cancer. 2003;36(4):353–60.

    Article  CAS  Google Scholar 

  8. Hagemeijer A, Bartram CR, Smit EM, van Agthoven AJ, Bootsma D. Is the chromosomal region 9q34 always involved in variants of the Ph1 translocation? Cancer Genet Cytogenet. 1984;13(1):1–16.

    Article  CAS  Google Scholar 

  9. Aventin A, Mecucci C, Louwagie A, Schutyser J, Van den Berghe H. High-resolution banding in the cytogenetic analysis of chronic myeloid leukemia with a complex translocation. Sangre (Barc). 1987;32(1):6–11.

    CAS  PubMed  Google Scholar 

  10. Calabrese G, Stuppia L, Franchi PG, Peila R, Morizio E, Liberati AM, et al. Complex translocations of the Ph chromosome and Ph negative CML arise from similar mechanisms, as evidenced by FISH analysis. Cancer Genet Cytogenet. 1994;78(2):153–9.

    Article  CAS  Google Scholar 

  11. Gudi R, Elizalde A, Gogineni SK, Macera MJ, Badillo A, Verma RS. Characterization of a complex translocation [t(4;9;22)(p16;q34;q11)] in chronic myelogenous leukemia by fluorescence in situ hybridization technique. Cancer Genet Cytogenet. 1996;90(2):142–5.

    Article  CAS  Google Scholar 

  12. Morel F, Herry A, Le Bris MJ, Morice P, Bouquard P, Abgrall JF, et al. 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(2):115–20.

    Article  CAS  Google Scholar 

  13. Sheth FJ, Sheth JJ, Verhest A. A three way complex translocation (4; 9; 22) in two patients with chronic myelocytic leukemia. J Cancer Res Ther. 2005;1(2):108–10.

    Article  Google Scholar 

  14. Chauffaille Mde L, Bandeira AC, da Silva AS. Diversity of breakpoints of variant Philadelphia chromosomes in chronic myeloid leukemia in Brazilian patients. Rev Bras Hematol Hemoter. 2015;37(1):17–20.

    Article  Google Scholar 

  15. Markovic VD, Bouman D, Bayani J, Al-Maghrabi J, Kamel-Reid S, Squire JA. Lack of BCR/ABL reciprocal fusion in variant Philadelphia chromosome translocations: a use of double fusion signal FISH and spectral karyotyping. Leukemia. 2000;14(6):1157–60.

    Article  CAS  Google Scholar 

  16. Inazawa J, Ariyama T, Abe T, Druck T, Ohta M, Huebner K, et al. PTPN13, a fas-associated protein tyrosine phosphatase, is located on the long arm of chromosome 4 at band q21.3. Genomics. 1996;31(2):240–2.

    Article  CAS  Google Scholar 

  17. Hendrickx W, Simeone I, Anjum S, Mokrab Y, Bertucci F, Finetti P, et al. Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis. Oncoimmunology. 2017;6(2):e1253654.

    Article  Google Scholar 

  18. Hussey DJ, Nicola M, Moore S, Peters GB, Dobrovic A. The (4;11)(q21;p15) translocation fuses the NUP98 and RAP1GDS1 genes and is recurrent in T-cell acute lymphocytic leukemia. Blood. 1999;94(6):2072–9.

    Article  CAS  Google Scholar 

  19. Gu Y, Nakamura T, Alder H, Prasad R, Canaani O, Cimino G, et al. The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell. 1992;71(4):701–8.

    Article  CAS  Google Scholar 

  20. Bompard G, Martin M, Roy C, Vignon F, Freiss G. Membrane targeting of protein tyrosine phosphatase PTPL1 through its FERM domain via binding to phosphatidylinositol 4,5-biphosphate. J Cell Sci. 2003;116(Pt 12):2519–30.

    Article  CAS  Google Scholar 

  21. Hughes A, Yong ASM. Immune effector recovery in chronic myeloid leukemia and treatment-free remission. Front Immunol. 2017;8:469.

    Article  Google Scholar 

  22. Morrissey J, Tkachuk DC, Milatovich A, Francke U, Link M, Cleary ML. A serine/proline-rich protein is fused to HRX in t(4;11) acute leukemias. Blood. 1993;81(5):1124–31.

    Article  CAS  Google Scholar 

  23. Konig M, Reichel M, Marschalek R, Haas OA, Strehl S. A highly specific and sensitive fluorescence in situ hybridization assay for the detection of t(4;11)(q21;q23) and concurrent submicroscopic deletions in acute leukaemias. Br J Haematol. 2002;116(4):758–64.

    Article  CAS  Google Scholar 

  24. Bueno C, Montes R, Catalina P, Rodriguez R, Menendez P. Insights into the cellular origin and etiology of the infant pro-B acute lymphoblastic leukemia with MLL-AF4 rearrangement. Leukemia. 2011;25(3):400–10.

    Article  CAS  Google Scholar 

  25. Meyer C, Burmeister T, Groger D, Tsaur G, Fechina L, Renneville A, et al. The MLL recombinome of acute leukemias in 2017. Leukemia. 2018;32(2):273–84.

    Article  CAS  Google Scholar 

  26. Montes R, Ayllon V, Gutierrez-Aranda I, Prat I, Hernandez-Lamas MC, Ponce L, et al. Enforced expression of MLL-AF4 fusion in cord blood CD34+ cells enhances the hematopoietic repopulating cell function and clonogenic potential but is not sufficient to initiate leukemia. Blood. 2011;117(18):4746–58.

    Article  CAS  Google Scholar 

  27. Liu S, Li Q, Pang W, Bo L, Qin S, Liu X, et al. A new complex variant t(4;15;17) in acute promyelocytic leukemia: fluorescence in situ hybridization confirmation and literature review. Cancer Genet Cytogenet. 2001;130(1):33–7.

    Article  CAS  Google Scholar 

  28. Tirro E, Massimino M, Stella S, Zammit V, Consoli ML, Pennisi MS, et al. Efficacy of nilotinib in a CML patient expressing the three-way complex variant translocation t(2;9;22). Anticancer Res. 2019;39(7):3893–9.

    Article  CAS  Google Scholar 

  29. 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(2):97–106.

    Article  CAS  Google Scholar 

  30. Richebourg S, Eclache V, Perot C, Portnoi MF, Van den Akker J, Terre C, et al. Mechanisms of genesis of variant translocation in chronic myeloid leukemia are not correlated with ABL1 or BCR deletion status or response to imatinib therapy. Cancer Genet Cytogenet. 2008;182(2):95–102.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This work was supported by JSPS KAKENHI Grant-in-Aid for Scientific Research (C) grant number JP20K08704 (T.T), The Japanese Society of Hematology Research Grant (T.T), Friends of Leukemia Research Fund (T.T.), and Takeda Science Foundation Research Grant (T.T)

Author information

Author notes

  1. Yuka Torii and Kana Nanjo contributed equally to this study

Authors and Affiliations

  1. Department of Internal Medicine III, Division of Hematology and Cell Therapy, Yamagata University faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan

    Yuka Torii, Tomomi Toubai, Masashi Hosokawa, Ryo Sato, Akane Yamada, Keiko Aizawa, Masahito Himuro, Satoshi Ito, Masakazu Yamamoto & Kenichi Ishizawa

  2. Faculty of Medicine, Yamagata University, Yamagata, Japan

    Kana Nanjo

  3. Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Medical School, Ann Arbor, MI, USA

    John Magenau & Ryan Wilcox

Authors
  1. Yuka Torii
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kana Nanjo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomomi Toubai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masashi Hosokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ryo Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Akane Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Keiko Aizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masahito Himuro
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Satoshi Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Masakazu Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. John Magenau
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ryan Wilcox
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kenichi Ishizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YT and TT diagnosed and treated the patient and wrote the article. KN wrote the article. RW, JM, and KI provided instructions for writing this article. MHo, RS, AY, KA, MHi, SI, and MY treated the patient. All authors read and approved the final manuscript .

Corresponding author

Correspondence to Tomomi Toubai.

Ethics declarations

Ethics approval and consent to participate

The Ethical Review Committee of Yamagata University Faculty of Medicine approved this work and its publication (committee’s reference no. 2019-S-102).

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Torii, Y., Nanjo, K., Toubai, T. et al. A unique three-way Philadelphia chromosome variant t(4;9;22)(q21;q34;q11.2) in a newly diagnosed patient with chronic phase chronic myeloid leukemia: a case report and review of the literature. J Med Case Reports 15, 285 (2021). https://doi.org/10.1186/s13256-021-02885-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13256-021-02885-4

Keywords

Journal of Medical Case Reports

ISSN: 1752-1947