Myeloproliferative neoplasm with ETV6-ABL1 fusion: a case report and literature review

Abstract

ETV6-ABL1 is a rare gene fusion with oncogenic properties, reported so far in 28 patients presenting a variety of haematological malignancies associated with clinical outcome, including chronic myeloid leukaemia (CML), acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) and chronic myeloproliferative neoplasm (cMPN). Here we report on a 46-year-old female who presented with Philadelphia negative CML, positive for the ETV6-ABL1 fusion. Whole genome screening carried out with oligonucleotide arrays showed a subtle loss at 12p13 and cryptic imbalances within the 9q34.3 region in a highly unstable genome. FISH mapping with custom BAC probes identified two breakpoints 5 Mb apart within the 9q34 region, together with a break at 12p13. While FISH with commercial BCR-ABL1 probes failed to detect any ABL1 changes, the ETV6 break-apart probe conclusively identified the ETV6-ABL1 fusion thus determining the probe's role as the primary diagnostic FISH test for this chimeric oncogene. In addition, we confirm the association of the ETV6-ABL1 fusion with imatinib resistance reported so far in three other patients, while recording excellent response to the 2nd generation tyrosine kinase inhibitor (TKI) nilotinib. In summary, we highlight the value of ETV6 FISH as a diagnostic test and the therapy resistance of ETV6-ABL1 positive disorders to imatinib.

Figure 1

Representative Philadelphia negative metaphase bone marrow cell with a t(9;12)(q34;p13) translocation. (a) G-banded karyotype; (b) FISH analysis demonstrates lack of BCR-ABL1 fusion but reveals a small third signal from the ABL1 probe (arrow) and; (c) The ETV6 split signal (arrowed in red) on der(9)t(9;12) from the break-apart FISH probe shows the gene rearrangement and confirms G banding results. The red/green fusion signal marks the normal gene.

Figure 2

FISH mapping of 9q34 and 12p13 regions in t (9;12)(q34;p13). (a) Diagram of 9q34 (top) and 12p13 chromosome regions with a map of the BAC clones used for FISH analysis. Red arrows indicate breakpoint positions in 9q34.12, 9q34.3 and 12p13.2; (b) Exons 2-11 of the ABL1 (RP11-83 J21 in red) on der(9)t(9;12) co-localizing with the 5’ part of the ETV6 gene (RP11-418C2 in green) and (c) The break at 9q34.3, 5.63 Mb distal to ABL1, is flanked proximally by RP11-707O3 (green) which houses the NOTCH1 gene and remains in der(9)t(9;12) and distally by RP11-678D10 (red) which has moved to der(12)t(9;12) (arrowed).

Figure 3

Representative cells with FISH signals showing the cryptic three way rearrangement of ABL1, NOTCH1 and ETV6 associated with t(9;12)(q34;p13). BAC clones covering the regions of interest are as follows: ABL1 (RP11-83 J21 & RP11-57C19, in red), NOTCH1 (RP11-707O3&RP11-678D10, in blue) and ETV6 (RP11-418C2 & RP11-36 K5, in green) (a) FISH signals from all three genes - ETV6, ABL1 and NOTCH1 - cluster at der(9)t(9;12) in a metaphase cell (arrows) (b) in a non-dividing cell the ETV6 (exons 1-5)/ABL1 (exons 2-11) fusion(green/red arrow) is separated from the co-localized ABL1 (exons 1b-2) and NOTCH1 signals (red/blue arrows); while ABL1 and NOTCH1 signals (~5.6 Mb apart) mark the normal 9 homologue and signals from ETV6 (green) and RP11-678D10 (downstream of NOTCH1, blue) co-hybridize at der(12)t(9;12).

Figure 4

Formation of a fusion between the ABL1 and ETV6 genes with opposite chromosomal orientation via two events: (i) firstly, a balanced t(9;12)(q34;p13) results in the juxtaposition of part of the ETV6 gene (exons 1-5) in the vicinity of NOTCH1 at 9q34.3 on der(9)t(9;12) while ABL1 remains intact followed by (ii) an inversion within the 9q34 segment of der(9)t(9;12) after breaks at 9q34.12 (within ABL1, upstream of exon 2) and 9q34.3. This leads to formation of an ETV6-ABL1 fusion gene but leaves the NOTCH1 gene intact.