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Leuk Res Rep. 2017; 7: 17–19.
Published online 2017 January 31. doi:  10.1016/j.lrr.2017.01.003
PMCID: PMC5328719

A case of acute myeloid leukemia with e6a2 BCR-ABL fusion transcript acquired after progressing from chronic myelomonocytic leukemia

Abstract

Philadelphia (Ph) chromosome is a cytogenetic hallmark of chronic myeloid leukemia (CML). Most patients with CML harbor either the e13a2 or e14a2 BCR-ABL fusion product, while a small subset of the cases expresses e1a2 or e19a2 transcripts. We report a patient with chronic myelomonocytic leukemia (CMML), initially Ph chromosome negative at presentation, with rapid disease progression to acute myeloid leukemia (AML) and appearance of Ph chromosome and BCR-ABL e6a2, a very uncommon fusion transcript. The AML was refractory to treatment with subsequent emergence and dominance of a Ph negative leukemic clone. The patient expired shortly after disease progression.

Keywords: CMML, BCR-ABL e6a2, AML transformation

Philadelphia (Ph) chromosome results from the reciprocal translocation t(9;22)(q34.1;q11.2), and is a diagnostic feature for chronic myeloid leukemia (CML). In most cases, the breakpoint in BCR occurs in M-bcr region, leading to production of e13a2 and/or e14a2 fusion transcripts. The breakpoints infrequently occur in either m-bcr or μ-bcr, producing e1a2 or long e19a2 fusion transcripts. Several other variant transcripts, such as e8a2, e13a3, e14a3, and e6a2 have also been identified and account for <1% of CML cases. Late appearing Ph chromosome may be acquired over the course of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) or MDS, representing disease progression and often signifying poor prognosis. In this report we describe a patient with chronic myelomonocytic leukemia (CMML), a subtype of MDS/MPN, which progressed to AML with gain of the rare BCR-ABL1 fusion transcript e6a2 and died shortly of tumor lysis syndrome.

Fig. 1.
A; larger BCR-ABL1 fusion product is amplified by multiplex PCR, which is confirmed to be e6a2 by Sanger sequencing. B; Sanger sequencing (reverse read) showed the fusion is between BCR exon 6 and ABL1 exon 2 (corresponding forward read is illustrated ...

This report illustrates an unusual case of CMML which transformed to AML rapidly with emergence of the rare BCR-ABL1 e6a2 fusion transcript. The possibility CML in blasts crisis was excluded as the CMML biopsy showed dysgranulopoiesis and lacked Ph chromosome and BCR-ABL1 fusion transcript.

CML with BCR-ABL1 e6a2 fusion transcript appears to be associated with more aggressive clinical features, including accelerated/blastic phase on presentation [5], [7], rapid disease progression [1], [3], [8], and imatinib treatment failure [1], [7], [8]. Their response to TKI treatment is variable (Table 1). Briefly, 3 of 7 patients who received a TKI (#5, #6, #10) responded to imatinib, nilotinib, or dasatinib; with disease stabilization or hematologic/molecular remission. Three patients (#7–9) showed persistent/progressive disease, while one died early from infection (#3). The other reported CMML case (#11) showed molecular response to imatinib after 3 months, although long term followup is not available. Our patient is unique since although his Ph+ clone drastically diminished in response to nilotinib (95% to 3.4%), his blast burden remained high (80%) with dominance of the Ph negative clone. Although it is tempting to speculate that the Ph negative clone may have been selected from suppression of the Ph+ clone by nilotinib, the patient’s rapidly progressive disease may be due to an inherently aggressive biological behavior of his antecedent CMML and unrelated to TKI therapy, a notion that appears to be supported by the presence of RUNX1 and TP53 mutations in the CMML specimen.

Table 1
Clinicopathologic features of reported chronic myeloid neoplasm cases harboring e6a2 fusion transcript.

It was hypothesized that shorter BCR-ABL transcripts are associated with a more aggressive clinical course due to lack of important regulatory bcr sequences within the fusion proteins [2]. Specifically in e6a2 transcript, the breakpoint in bcr intron 6 may result in partial loss of GEF/dbl-like domain that mediates interaction with several Ras-like G proteins involved in cell proliferation and signal transduction, which leads to enhanced tyrosine kinase activity of the BCR-ABL1 fusion protein.

In summary, our case illustrates the importance of combining conventional karyotype/FISH and appropriate molecular studies to detect rare BCR-ABL fusion transcripts such as e6a2. As a late appearing secondary Ph chromosome is usually considered a poor prognostic factor in hematopoietic malignancies, individualized therapeutic strategies such as newer TKIs and allogeneic stem cell transplantation may be warranted.

References

1. Schnittger S., Bacher U., Kern W., Haferlach T., Hertenstein B., Haferlach C. A new case with rare e6a2 BCR-ABL fusion transcript developing two new resistance mutations during imatinib mesylate, which were replaced by T315I after subsequent dasatinib treatment. Leukemia. 2008;22:856–858. [PubMed]
2. Colla S., Sammarelli G., Voltolini S., Crugnola M., Sebastio P., Giuliani N. e6a2 BCR-ABL transcript in chronic myeloid leukemia: is it associated with aggressive disease? Haematologica. 2004;89:611–613. [PubMed]
3. Hochhaus A., Reiter A., Skladny H. A novel BCR-ABL fusion gene (e6a2) in a patient with Philadelphia chromosome-negative chronic myelogenous leukemia. Blood. 1996;88:2236–2240. [PubMed]
4. Dupont M., Jourdan E., Chiesa J. Identification of E6A2 BCR-ABL fusion in a Philadelphia-positive CML. Leukemia. 2000;14:2011–2012. [PubMed]
5. Schultheis B., Wang L., Clark R.E., Melo J.V. BCR-ABL with an e6a2 fusion in a CML patient diagnosed in blast crisis. Leukemia. 2003;17:2054–2055. [PubMed]
6. Popovici C., Cailleres S., David M., Lafage-Pochitaloff M., Sainty D., Mozziconacci M.J. E6a2 BCR-ABL fusion with BCR exon 5-deleted transcript in a Philadelphia positive CML responsive to Imatinib. Leuk Lymphoma. 2005;46:1375–1377. [PubMed]
7. Vefring H.K., Gruber F.X., Wee L. Chronic myelogenous leukemia with the e6a2 BCR-ABL and lacking imatinib response: presentation of two cases. Acta Haematol. 2009;122:11–16. [PubMed]
8. Langabeer S.E., Crampe M., Kelly J., Fadalla K., Connaghan G., Conneally E. Nilotinib and allogeneic stem cell transplantation in a chronic myeloid leukemia patient with e6a2 and e1a2 BCR-ABL transcripts. Leuk. Res. 2010;34:e204–205. [PubMed]
9. Hayette S., Tigaud I., Thomas X. Identification of a rare e6a2 BCR-ABL fusion gene during the disease progression of chronic myelomonocytic leukemia: a case report. Leukemia. 2004;18:1735–1736. [PubMed]
10. Roti G., La Starza R., Gorello P. e6a2 BCR/ABL1 fusion with cryptic der(9)t(9;22) deletions in a patient with chronic myeloid leukemia. Haematologica. 2005;90:1139–1141. [PubMed]

Articles from Leukemia Research Reports are provided here courtesy of Elsevier