t(4;12)(q12;p13) ETV6-rearranged AML without eosinophilia does not involve PDGFRA: relevance for imatinib insensitivity
Autor: | Sarah B. Mueller, Marlise R. Luskin, Long P. Le, Hetal D. Marble, Paola Dal Cin, Daniel J. DeAngelo, Dora Dias-Santagata, Valentina Nardi, Jochen K. Lennerz, Matthew Weinstock, Andrew M. Brunner, Anthony J. Iafrate, Richard Stone |
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Rok vydání: | 2021 |
Předmět: |
business.industry
Chromosome Myeloid leukemia Receptor Protein-Tyrosine Kinases Chromosomal translocation Imatinib Hematology PDGFRA digestive system diseases ETV6 Leukemia Myeloid Acute Eosinophilia Cancer research medicine Imatinib Mesylate Humans medicine.symptom business Gene In Situ Hybridization Fluorescence medicine.drug Retrospective Studies |
Zdroj: | Blood advances. 6(3) |
ISSN: | 2473-9537 |
Popis: | Acute myeloid leukemia (AML) with t(4;12)(q12;p13) translocation is rare and often associated with an aggressive clinical course and poor prognosis. Previous reports based on fluorescence in situ hybridization (FISH) analysis have suggested that ETV6::PDGFRA fusions are present in these patients, despite the absence of eosinophilia, which is typically found in other hematopoietic malignancies with PDGFRA-containing fusions. We first detected an ETV6-SCFD2 fusion by targeted RNA sequencing in a patient with t(4;12)(q12;p13) who had been diagnosed with an ETV6-PDGFRA fusion by FISH analysis but failed to respond to imatinib. We then retrospectively identified 4 additional patients with AML and t(4;12)(q12;p13) with apparent ETV6-PDGFRA fusions using chromosome and FISH analysis and applied targeted RNA sequencing to archival material. We again detected rearrangements between ETV6 and non-PDGFRA 4q12 genes, including SCFD2, CHIC2, and GSX2. None of the 3 patients who received imatinib based on the incorrect assumption of an ETV6-PDGFRA fusion responded. Our findings highlight the importance of using a sequencing-based assay to confirm the presence of targetable gene fusions, particularly in genomic regions, such as 4q12, with many clinically relevant genes that are too close to resolve by chromosome or FISH analysis. Finally, combining our data and review of the literature, we show that sequence-confirmed ETV6-PDGFRA fusions are typically found in eosinophilic disorders (3/3 cases), and patients with t(4;12)(q12;p13) without eosinophilia are found to have other 4q12 partners on sequencing (17/17 cases). |
Databáze: | OpenAIRE |
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