Zaliova M, Moorman AV, Cazzaniga G, Stanulla M, Harvey RC, Roberts KG, Heatley SL, Loh ML, Konopleva M, Chen IM, Zimmermannova O, Schwab C, Smith O, Mozziconacci MJ, Chabannon C, Kim M, Falkenburg JH, Norton A, Marshall K, Haas OA, Starkova J, Stuchly J, Hunger SP, White D, Mullighan CG, Willman C, Stary J, Trka J, Zuna J. Haematologica. 2016 May 26. doi:10.3324/haematol.2016.144345 [Epub ahead of print]. IF: 6.67
MUDr. Markéta Kubričanová Žaliová, Ph.D., Department of Paediatric Haematology and Oncology
Abstract
To characterize the incidence, clinical features and genetics of ETV6-ABL1 leukemias, representing targetable kinase-activating lesion, we analyzed 44 new and published ETV6-ABL1 cases (22 acute lymphoblastic leukemias (13 children, 9 adults) and 22 myeloid malignancies (18 myeloproliferative neoplasms, 4 acute myeloid leukemias)). 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. Systemic screening of >4500 cases revealed that in acute lymphoblastic leukemia ETV6-ABL1 is rare in childhood (0.17% cases) and slightly more prevalent in adults (0.38%). There is no systematic screening in 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 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 samples clustered in close vicinity to BCR-ABL1 cases. All but one ETV6-ABL1 ALL were classified as BCR-ABL1-like by a standardized assay. Over 60% of patients died irrespective of the disease or age subgroup examined. In conclusion, ETV6-ABL1 fusion occurs in lymphoid and myeloid leukemia and its 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 in these patients.
