Myeloproliferative Neoplasm Driven by ETV6-ABL1 in an Adolescent with Recent History of Burkitt Leukemia

Abstract

ETV6-ABL1 gene fusion is a rare genetic rearrangement in a variety of malignancies, including myeloproliferative neoplasms (MPN), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). Here, we report the case of a 16-year-old male diagnosed with a MPN, 7 months post-completion of treatment for Burkitt leukaemia. RNA sequencing analysis confirmed the presence of an ETV6-ABL1 fusion transcript, with an intact, in-frame ABL tyrosine-kinase domain. Of note, secondary ETV6-ABL1-rearranged neoplastic diseases have not been reported to date. The patient was started on a tyrosine kinase inhibitor (TKI; imatinib) and, subsequently, underwent a 10/10 matched unrelated haematopoietic stem cell transplant. He is disease-free five years post-transplant. Definitive evidence of the prognostic influence of the ETV6-ABL1 fusion in haematological neoplasms is lacking; however, overall data suggest that it is a poor prognostic factor, particularly in patients with ALL and AML. The presence of this ETV6-ABL1 fusion should be more routinely investigated, especially in patients with a CML-like picture. More routine use of whole-genome and RNA sequencing analyses in clinical diagnostic care, in conjunction with conventional cytogenetics, will facilitate these investigations.

Keywords: myeloproliferative syndrome; oncology; pediatric malignancies.

Figure 1

(A) Representative karyotype from the blood sample obtained at initial diagnosis with Burkitt Leukaemia (left panel), demonstrating a t(8;14) and duplication of 1q. Interphase FISH analysis with a dual colour breakapart probe for the MYC gene (8q24.1) showed MYC gene rearrangement in the majority of cells (upper right panel). After the patient subsequently presented with MPN, BCR-ABL1 FISH performed on an archived Burkitt Leukaemia sample yielded normal results (lower right panel). (B) By G-band analysis of the myeloproliferative neoplasm, the karyotype appeared normal. Sequential BCR-ABL1 metaphase FISH analysis on G-banded cells showed insertion of the ABL1 signal into 12p13, with no involvement of the BCR gene (left panel). Metaphase FISH analysis using an ABL1 breakapart FISH probe (right panel) showed the insertion of 3′ABL1 into 12p13. Results of the ETV6 breakapart as well as the subtelomeric 9q and 12p FISH testing were normal, consistent with an insertion mechanism rather than a translocation mechanism in the generation of the ETV6-ABL1 fusion identified by molecular analysis.

Figure 1

(A) Representative karyotype from the blood sample obtained at initial diagnosis with Burkitt Leukaemia (left panel), demonstrating a t(8;14) and duplication of 1q. Interphase FISH analysis with a dual colour breakapart probe for the MYC gene (8q24.1) showed MYC gene rearrangement in the majority of cells (upper right panel). After the patient subsequently presented with MPN, BCR-ABL1 FISH performed on an archived Burkitt Leukaemia sample yielded normal results (lower right panel). (B) By G-band analysis of the myeloproliferative neoplasm, the karyotype appeared normal. Sequential BCR-ABL1 metaphase FISH analysis on G-banded cells showed insertion of the ABL1 signal into 12p13, with no involvement of the BCR gene (left panel). Metaphase FISH analysis using an ABL1 breakapart FISH probe (right panel) showed the insertion of 3′ABL1 into 12p13. Results of the ETV6 breakapart as well as the subtelomeric 9q and 12p FISH testing were normal, consistent with an insertion mechanism rather than a translocation mechanism in the generation of the ETV6-ABL1 fusion identified by molecular analysis.

Figure 2

Circos plots generated from WGS of the Burkitt Leukaemia (left) and MPN (right) samples. Both samples represent diagnostic specimens (peripheral blood for the Burkitt leukaemia and bone marrow aspirate for the MPN). ETV6-ABL1 rearrangement (chr12:12025863-chr9:133674524) was confirmed only in the MPN sample.