t(4;12)(q12;p13) ETV6-rearranged AML without eosinophilia does not involve PDGFRA: relevance for imatinib insensitivity

Abstract

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 previously been diagnosed with an ETV6-PDGFRA fusion by FISH analysis but failed to respond to imatinib. We then retrospectively identified four additional AML patients with 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 three 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 of 3 cases), and patients with t(4;12)(q12;p13) without eosinophilia are found to have other 4q12 partners on sequencing (17 of 17 cases).

Mapeo óptico del genoma: fundamentos tecnológicos y aplicaciones en neoplasias hematológicas

“…Algunos ejemplos descritos en la literatura son t(9;22)(q34;q11.2), que no implica BCR::ABL1 o bien t(4;12)(q12;p13) con supuesto reordenamiento ETV6::PDGFRA que en realidad no afecta a PDGFRA. En estos casos, el OGM permitió identificar con mayor resolución estas anomalías y poder explicar el comportamiento clínico inesperado de los pacientes que no respondían al tratamiento con inhibidores de la tirosina cinasa 41 .…”

Optical genome mapping: technical basis and applications in hematological malignancies

“…Examples described in the medical literature include t(9;22)(q34;q11.2), which does not involve BCR::ABL1, or t(4;12)(q12;p13) with an alleged ETV6::PDGFRA rearrangement that actually does not affect PDGFRA. In these instances, OGM allowed for higher-resolution identification of these abnormalities and explained the unexpected clinical behavior of patients who remained unresponsive to tyrosine kinase inhibitor treatment 41 .…”

The international consensus classification of eosinophilic disorders and systemic mastocytosis

“…Importantly, some AML with t(4;12)(q12;p13) have been shown to carry a PDGFRA rearrangement by FISH but insensitive to imatinib. A sequencing‐based assay 30 revealed ETV6 with fusion genes such as SCFD2 , CHIC2 , and GSX2 other than PDGFRA at 4q12. These genes are in 4q12 genomic region that are too close to be resolved by chromosome or FISH analysis.…”