Characterization of leukemias with ETV6-ABL1 fusion

Abstract

T o characterize the incidence, clinical features and genetics of ETV6-ABL1 leukemias, representing targetable kinase-activating lesions, we analyzed 44 new and published cases of ETV6-ABL1-positive hematologic malignancies [22 cases of acute lymphoblastic leukemia (13 children, 9 adults) and 22 myeloid malignancies (18 myeloproliferative neoplasms, 4 acute myeloid leukemias)]. The presence of the ETV6-ABL1 fusion was ascertained by cytogenetics, fluorescence in-situ hybridization, reverse transcriptase-polymerase chain reaction and RNA sequencing. Genomic and gene expression profiling was performed by single nucleotide polymorphism and expression arrays. Systematic screening of more than 4,500 cases revealed that in acute lymphoblastic leukemia ETV6-ABL1 is rare in childhood (0.17% cases) and slightly more common in adults (0.38%). There is no systematic screening of myeloproliferative neoplasms; however, the number of ETV6-ABL1-positive cases and the relative incidence of acute lymphoblastic leukemia and myeloproliferative neoplasms suggest that in adulthood ETV6-ABL1 is more common in BCR-ABL1-negative chronic myeloid leukemia-like myeloproliferations than in acute lymphoblastic leukemia. The genomic profile of ETV6-ABL1 acute lymphoblastic leukemia resembled that of BCR-ABL1 and BCR-ABL1-like cases with 80% of patients having concurrent CDKN2A/B and IKZF1 deletions. In the gene expression profiling all the ETV6-ABL1-positive samples clustered in close vicinity to BCR-ABL1 cases. All but one of the cases of ETV6-ABL1 acute lymphoblastic leukemia were classified as BCR-ABL1-like by a standardized assay. Over 60% of patients died, irrespectively of the disease or age subgroup examined. In conclusion, ETV6-ABL1 fusion occurs in both lymphoid and myeloid leukemias; the genomic profile and clinical behavior resemble BCR-ABL1-positive malignancies, including the unfavorable prognosis, particularly of acute leukemias. The poor outcome suggests that treatment with tyrosine kinase inhibitors should be considered for patients with this fusion.

Myeloid neoplasms with eosinophilia

“…Zaliova et al recently reported on the incidence, clinical features, and genetics of ETV6-ABL1 leukemias in 44 cases. 94 Overall, these cases are strongly reminiscent of BCR-ABL1-positive neoplasms. Phenotypes included ALL (n 5 22: children, n 5 13; adults, n 5 9) and myeloid neoplasms (n 5 22: MPN, n 5 18; AML, n 5 4).…”

“…Only a combination of ETV6 and ABL1 probes, targeted RT-PCR, or RNAseq can reliably identify the fusion. 94 In children, the clinical phenotype of ETV6-ABL1-positive patients is predominantly de novo ALL; however, similar to all other TK fusion genes in adults, various AML and chronic myeloid/lymphoid phenotypes have been described. Zaliova et al recently reported on the incidence, clinical features, and genetics of ETV6-ABL1 leukemias in 44 cases.…”

“…Patients with ETV6-ABL1-positive de novo or secondary acute leukemias/blast phase have a very poor prognosis, despite TKI therapy, with median survival of approximately 1 year. 94 …”

“…Of interest, eosinophilia was present in all MPN and AML cases, but only four of 13 ALL cases. 94 In adults, the prognosis of acute leukemias is very poor, whereas patients with MPN have significantly better survival. Among those evaluable, more than 80% of patients died because of disease progression or relapse.…”

“…[90][91][92][93] Importantly, the creation of the ETV6-ABL1 fusion requires at least 3 chromosomal breaks, usually a cryptic insertion, to generate an in-frame fusion gene. 93,94 Routine karyotyping is therefore usually inconclusive, and FISH can miss the small insertions. Only a combination of ETV6 and ABL1 probes, targeted RT-PCR, or RNAseq can reliably identify the fusion.…”