Acute myeloid leukemia with t(3;21)(q26.2;q22) developing following low‑dose methotrexate therapy for rheumatoid arthritis and expressing two AML1/MDS1/EVI1 fusion proteins: A case report

Tanaka,Keisuke; Oshikawa,Gaku; Akiyama,Hiroki; Ishida,Shinya; Nagao,Toshikage; Yamamoto,Masahide; Miura,Osamu

doi:10.3892/ol.2017.6151

Acute myeloid leukemia with t(3;21)(q26.2;q22) developing following low‑dose methotrexate therapy for rheumatoid arthritis and expressing two AML1/MDS1/EVI1 fusion proteins: A case report

Authors:
- Keisuke Tanaka
- Gaku Oshikawa
- Hiroki Akiyama
- Shinya Ishida
- Toshikage Nagao
- Masahide Yamamoto
- Osamu Miura
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Affiliations: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113‑8510, Japan
Published online on: May 10, 2017 https://doi.org/10.3892/ol.2017.6151
Pages: 97-102
Copyright: © Tanaka et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The t(3;21)(q26.2;q22) translocation is a rare chromosomal abnormality exhibited almost exclusively in therapy‑related myelodysplastic syndrome/acute myeloid leukemia (t‑MDS/AML) or in the blastic crisis phase of chronic myelogenous leukemia, which results in the fusion of the runt related transcription factor 1 (RUNX1, also called AML1) gene at 21q22 to the myelodysplasia syndrome 1 (MDS1)‑ecotropic virus integration site 1 (EVI1) complex locus (MECOM) at 3q26.2, generating various fusion transcripts, including AML1/MDS1/EVI1 (AME). The present study examined the case of an 84‑year‑old Japanese woman who developed t‑MDS/AML with t(3;21)(q26.2;q22) subsequent to receiving low‑dose methotrexate (MTX) treatment for rheumatoid arthritis. Following treatment with MTX for 6 years, the patient developed anemia and neutropenia, and MTX was discontinued. A total of 3 years later, the patient was diagnosed with MDS with t(3;21)(q26.2;q22) and del (5q), which progressed rapidly to AML within 3 months. The patients was subsequently treated with azacitidine and cytarabine chemotherapy, but succumbed to the disease 6 months after diagnosis. Sequencing analysis of the nested reverse transcription‑PCR products from the leukemic cells revealed the expression of two types of alternatively‑spliced AME transcripts with or without RUNX1 exon 6 sequences. Western blot analysis of the leukemic cells of the patient additionally revealed that the corresponding AME fusion protein products were expressed at high levels, and that these cells also prominently expressed CCAAT/enhancer‑binding protein α, the repression of which has been reported to be involved in leukemogenesis mediated by AME. To the best of our knowledge, the case discussed in the present study represents the first report of MDS/AML with t(3;21)(q26.2;q22) developing following low‑dose MTX therapy for rheumatoid arthritis. Nonetheless, the clinical and molecular features of the patient in the present study were representative of those patients who typically develop this disease following exposure to chemotherapy or radiotherapy for primary malignancy, which implicates MTX in the pathogenesis of t‑MDS/AML. Moreover, we confirmed the expression of two AME fusion proteins for the first time in primary leukemic cells and analyzed several cellular factors implicated in AME‑mediated leukemogenesis to gain some insight into its molecular mechanisms.

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1	Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J and Vardiman JW: WHO classification of tumours of haematopoietic and lymphoid tissues. 2. 4th. IARC; 2008
2	Nucifora G, Laricchia-Robbio L and Senyuk V: EVI1 and hematopoietic disorders: History and perspectives. Gene. 368:1–11. 2006. View Article : Google Scholar : PubMed/NCBI
3	Yin CC, Cortes J, Barkoh B, Hayes K, Kantarjian H and Jones D: t(3;21)(q26;q22) in myeloid leukemia: An aggressive syndrome of blast transformation associated with hydroxyurea or antimetabolite therapy. Cancer. 106:1730–1738. 2006. View Article : Google Scholar : PubMed/NCBI
4	Maki K, Yamagata T and Mitani K: Role of the RUNX1-EVI1 fusion gene in leukemogenesis. Cancer Sci. 99:1878–1883. 2008.PubMed/NCBI
5	Li S, Yin CC, Medeiros LJ, Bueso-Ramos C, Lu G and Lin P: Myelodysplastic syndrome/acute myeloid leukemia with t(3;21)(q26.2;q22) is commonly a therapy-related disease associated with poor outcome. Am J Clin Pathol. 138:146–152. 2012. View Article : Google Scholar : PubMed/NCBI
6	Glass C, Wilson M, Gonzalez R, Zhang Y and Perkins AS: The role of EVI1 in myeloid malignancies. Blood Cell Mol Dis. 53:67–76. 2014. View Article : Google Scholar
7	Hinai AA and Valk PJ: Review: Aberrant EVI1 expression in acute myeloid leukaemia. Br J Haematol. 172:870–888. 2016. View Article : Google Scholar : PubMed/NCBI
8	Morishita K, Parker DS, Mucenski ML, Jenkins NA, Copeland NG and Ihle JN: Retroviral activation of a novel gene encoding a zinc finger protein in IL-3-dependent myeloid leukemia cell lines. Cell. 54:831–840. 1988. View Article : Google Scholar : PubMed/NCBI
9	Gröschel S, Sanders MA, Hoogenboezem R, De Wit E, Bouwman BA, Erpelinck C, van der Velden VH, Havermans M, Avellino R, van Lom K, et al: A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell. 157:369–381. 2014. View Article : Google Scholar : PubMed/NCBI
10	Yamazaki H, Suzuki M, Otsuki A, Shimizu R, Bresnick EH, Engel JD and Yamamoto M: A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression. Cancer Cell. 25:415–427. 2014. View Article : Google Scholar : PubMed/NCBI
11	Mitani K, Ogawa S, Tanaka T, Miyoshi H, Kurokawa M, Mano H, Yazaki Y, Ohki M and Hirai H: Generation of the AML1-EVI-1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia. EMBO J. 13:504–510. 1994.PubMed/NCBI
12	Nucifora G, Begy CR, Kobayashi H, Roulston D, Claxton D, Pedersen-Bjergaard J, Parganas E, Ihle JN and Rowley JD: Consistent intergenic splicing and production of multiple transcripts between AML1 at 21q22 and unrelated genes at 3q26 in (3;21)(q26;q22) translocations. Proc Natl Acad Sci USA. 91:pp. 4004–4008. 1994; View Article : Google Scholar : PubMed/NCBI
13	Motomura S, Fujisawa S, Tsunooka S, Fujimaki K, Harano H, Mohri H, Okubo T, Fujita H, Maruta A and Kodama F: Translocation (3;21)(q26;q22) in de novo acute myelogenous leukemia. Leukemia. 11:172–173. 1997. View Article : Google Scholar : PubMed/NCBI
14	Park TS, Choi JR, Yoon SH, Song J, Kim J, Kim SJ, Kwon O and Min YH: Acute promyelocytic leukemia relapsing as secondary acute myelogenous leukemia with translocation t(3;21)(q26;q22) and RUNX1-MDS1-EVI1 fusion transcript. Cancer Genet Cytogenet. 187:61–73. 2008. View Article : Google Scholar : PubMed/NCBI
15	Yang JJ, Cho SY, Suh JT, Lee HJ, Lee WI, Yoon HJ, Baek SK and Park TS: Detection of RUNX1-MECOM fusion gene and t(3;21) in a very elderly patient having acute myeloid leukemia with myelodysplasia-related changes. Ann Lab Med. 32:362–365. 2012. View Article : Google Scholar : PubMed/NCBI
16	Forghieri F, Bigliardi S, Morselli M, Potenza L, Fantuzzi V, Faglioni L, Nasillo V, Messerotti A, Paolini A and Luppi M: An unusual case of splenomegaly and increased lactate dehydrogenase heralding acute myeloid leukemia with eosinophilia and RUNX1-MECOM fusion transcripts. Leuk Res Rep. 3:83–85. 2014.PubMed/NCBI
17	Nogami A, Oshikawa G, Okada K, Fukutake S, Umezawa Y, Nagao T, Kurosu T and Miura O: FLT3-ITD confers resistance to the PI3K/Akt pathway inhibitors by protecting the mTOR/4EBP1/Mcl-1 pathway through STAT5 activation in acute myeloid leukemia. Oncotarget. 6:9189–9205. 2015. View Article : Google Scholar : PubMed/NCBI
18	Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 89:2079–2088. 1997.PubMed/NCBI
19	Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, et al: Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 120:2454–2465. 2012. View Article : Google Scholar : PubMed/NCBI
20	Malcovati L, Porta MG, Pascutto C, Invernizzi R, Boni M, Travaglino E, Passamonti F, Arcaini L, Maffioli M, Bernasconi P, et al: Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: A basis for clinical decision making. J Clin Oncol. 23:7594–7603. 2005. View Article : Google Scholar : PubMed/NCBI
21	Mitelman F, Johansson B and Mertens FE: Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer. http://cgap ncinihgov/Chromosomes/MitelmanFebruary 16–2016
22	Ichikawa A, Arakawa F, Kiyasu J, Sato K, Miyoshi H, Niino D, Kimura Y, Takeuchi M, Yoshida M, Ishibashi Y, et al: Methotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: Histology, Epstein-Barr virus, and clonality are important predictors of disease progression and regression. Eur J Haematol. 91:20–28. 2013. View Article : Google Scholar : PubMed/NCBI
23	Pointud P, Prudat M and Peron JM: Acute leukemia after low dose methotrexate therapy in a patient with rheumatoid arthritis. J Rheumatol. 20:1215–1216. 1993.PubMed/NCBI
24	Kerr L Dubin, Troy K and Isola L: Temporal association between the use of methotrexate and development of leukemia in 2 patients with rheumatoid arthritis. J Rheumatol. 22:2356–2358. 1995.PubMed/NCBI
25	Rosenthal NS and Farhi DC: Myelodysplastic syndromes and acute myeloid leukemia in connective tissue disease after single-agent chemotherapy. Am J Clin Pathol. 106:676–679. 1996. View Article : Google Scholar : PubMed/NCBI
26	Kolte B, Baer AN, Sait SN, O'Loughlin KL, Stewart CC, Barcos M, Wetzler M and Baer MR: Acute myeloid leukemia in the setting of low dose weekly methotrexate therapy for rheumatoid arthritis. Leuk Lymphoma. 42:371–378. 2001. View Article : Google Scholar : PubMed/NCBI
27	Choi BR, Ahn MJ, Lee WS, Kim TH, Bae SC and Jun JB: Acute erythroleukemia in a rheumatoid arthritis patient during low-dose methotrexate therapy. Rheumatol Int. 25:311–313. 2005. View Article : Google Scholar : PubMed/NCBI
28	Al-Anazi KA, Eltayeb KI, Bakr M and Al-Mohareb FI: Methotrexate-induced acute leukemia: Report of three cases and review of the literature. Clin Med Case Rep. 2:43–49. 2009.PubMed/NCBI
29	Sakai T, Tamura S, Miyoshi T, Nesumi N, Nagai K and Oshima K: Development of myeloid sarcoma after long-term methotrexate use for rheumatoid arthritis. Int J Hematol. 99:493–498. 2014. View Article : Google Scholar : PubMed/NCBI
30	Anderson LA, Pfeiffer RM, Landgren O, Gadalla S, Berndt SI and Engels EA: Risks of myeloid malignancies in patients with autoimmune conditions. Br J Cancer. 100:822–828. 2009. View Article : Google Scholar : PubMed/NCBI
31	Tokita K, Maki K and Mitani K: RUNX1/EVI1, which blocks myeloid differentiation, inhibits CCAAT-enhancer binding protein alpha function. Cancer Sci. 98:1752–1757. 2007. View Article : Google Scholar : PubMed/NCBI
32	Maicas M, Vázquez I, Vicente C, García-Sánchez MA, Marcotegui N, Urquiza L, Calasanz MJ and Odero MD: Functional characterization of the promoter region of the human EVI1 gene in acute myeloid leukemia: RUNX1 and ELK1 directly regulate its transcription. Oncogene. 32:2069–2078. 2013. View Article : Google Scholar : PubMed/NCBI
33	Helbling D, Mueller BU, Timchenko NA, Hagemeijer A, Jotterand M, Meyer-Monard S, Lister A, Rowley JD, Huegli B, Fey MF and Pabst T: The leukemic fusion gene AML1-MDS1-EVI1 suppresses CEBPA in acute myeloid leukemia by activation of Calreticulin. Proc Natl Acad Sci USA. 101:pp. 13312–13317. 2004; View Article : Google Scholar : PubMed/NCBI