Detection of rare reciprocal RUNX1 rearrangements by next‐generation sequencing in acute myeloid leukemia

Abstract

Reciprocal RUNX1 fusions are traditionally found in up to 10% of acute myeloid leukemia (AML) patients, usually associated with a translocation (8;21)(q22;q22) corresponding to the RUNX1-RUNX1T1 fusion gene. So far, alternative RUNX1 rearrangements have been reported only rarely in AML, and the few reports so far have focused on results based on cytogenetics, fluorescence in situ hybridization, and polymerase chain reaction. Acknowledging the inherent limitations of these diagnostic techniques, the true incidence of rare RUNX1 rearrangements may be underestimated. In this report, we present two cases of adult AML, in which we detected rare RUNX1 rearrangements not by conventional cytogenetics but rather by nextgeneration panel sequencing. These include t(16;21)(q24;q22)/RUNX1-CBFA2T3 and t(7;21)(p22;q22)/RUNX1-USP42, respectively. In both patients the AML was therapyrelated and associated with additional structural and numerical alterations thereby conferring bad prognosis. This is in line with previous reports on rare RUNX1 fusions in AML and emphasizes the clinical importance of their detection. In summary, our report not only confirms the clinical utility of NGS for diagnostics of rare reciprocal rearrangements in AML in a real-life scenario but also sheds light on the variety and complexity within AML. It further emphasizes the need for collection of additional cases for deepening insights on their clinical meaning as well as their frequency.acute myeloid leukemia, myeloid gene panel, new minimal residual disease marker, next-generation sequencing, rare RUNX1 rearrangements

Clonal Hematopoiesis after Autologous Stem Cell Transplantation Does Not Confer Adverse Prognosis in Patients with AML

“…Multiparameter flow cytometry as well as molecular methods are routinely used for diagnosis and screening for residual disease in AML patients. While recurrent mutations in genes such as FLT3 or NPM1 have been incorporated in risk assessment for a long time [1,3], the introduction of next-generation sequencing (NGS) into the hematologic routine has enabled the discovery of a multitude of additional and often novel mutations [5]. The detection of druggable mutations has also opened the door for customized treatment strategies, some of which were integrated in the European LeukemiaNet (ELN) risk assessment and treatment for patients with AML [1,6,7].…”

Next Generation Cytogenetics in Myeloid Hematological Neoplasms: Detection of CNVs and Translocations

“…Among all the alterations only detected by NGS, a cryptic rearrangement of the KMT2A gene was also observed. Rearrangements by NGS are usually analyzed on RNA samples [15,34,35]. Although the sensitivity reached is not enough to use it as a follow-up technique, the detection of rearrangements in seven cases by our custom-panel indicates that DNA designed panels could be a good alternative for the detection of frequent rearrangements at diagnosis of the myeloid disease.…”

Clinical potential of introducing next‐generation sequencing in patients at relapse of acute myeloid leukemia

“…Traditionally, AML‐relevant gene fusions ( RUNX1‐RUNX1T1 , CBFB‐MYH11 , and PML‐RARA ) have been detected using classical chromosome banding analysis, PCR techniques, and fluorescence in situ hybridization. RNA‐sequencing panels, such as the TrueSight RNA Fusion panel (Illumina) or the FusionPlex (Archer) now allow the simultaneous detection of over 300 relevant fusion transcripts in a single assay 8 . This unbiased approach comes with the additional benefit that previously unknown partner genes with potential prognostic or therapeutic value can be detected 9 .…”