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

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.

H2AFY is a novel fusion partner of MECOM in acute myeloid leukemia

“…High MECOM mRNA expression was observed in 10% of de novo AML, associated with a poor prognosis [2] . The MECOM gene can be rearranged with a variety of partner genes, such as ETV6 , RUNX1 , and so on [3,4] Organization (WHO) classification of myeloid neoplasms and acute leukemia recognized "AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2 , MECOM " as a distinct entity [5] . Herein, we identified H2AFY as a novel fusion gene partner of MECOM in a patient with AML.…”

A case mimicking chronic myeloid leukemia with t(8;22)(p11;q11)/BCR-FGFR1 and sequential transformation to B-acute lymphoblastic leukemia and acute myeloid leukemia

“…The secondary abnormality t(3;21)(q26.2;q22) which developed following therapy in our patient is a rare abnormality and occurs in < 1% of cases with AML/MDS, primarily t-MDS/AML or in the blast phase of CML. It has been reported that these abnormalities occur particularly after chemotherapy and are associated with a poor prognosis [21,22].…”

Cell models with inducible oncogenic translocations allow to evaluate the potential of drugs to favor secondary translocations

“…Thus, methotrexate use can increase the risk of secondary therapy‐related AML, and patients treated with methotrexate should be monitored for the development of AML. Noteworthy, the development of therapy‐related myelodysplastic syndrome/AML with t(8;21) and t(3;21) translocations was described in patients following low‐dose treatment with methotrexate for rheumatoid arthritis [ 6 ].…”