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Haematologica. 2019 Jan 10. pii: haematol.2018.204487. doi: 10.3324/haematol.2018.204487. [Epub ahead of print]

ERG deletions in childhood acute lymphoblastic leukemia with DUX4 rearrangements are mostly polyclonal, prognostically relevant and their detection rate strongly depends on method's sensitivity.

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CLIP - Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology;
CLIP - Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology.
Department of Pediatric Haematology-Oncology, Second Faculty of Medicine, Charles University, Prague.


ERG-deletions occur recurrently in acute lymphoblastic leukemia, especially in DUX4-rearranged subtype. The ERG-deletion was shown to positively impact prognosis of patients with IKZF1-deletion and its presence precludes assignment into IKZF1plus group, a novel high-risk category on AIEOP-BFM ALL trials. We analyzed the impact of different methods on ERG-deletion detection rate, evaluated ERG-deletion as a potential marker for DUX4-rearranged leukemia, studied its associations with molecular and clinical characteristics within this leukemia subtype and analyzed its clonality. Using single-nucleotide-polymorphism array, genomic polymerase-chain-reaction and amplicon-sequencing we found ERG-deletion in 34% (16/47), 66% (33/50) and 78% (39/50) of DUX4-rearranged leukemia, respectively. False negativity of ERG-deletion by single-nucleotide-polymorphism array caused IKZF1plus misclassification in 5 patients. No ERG-deletion was found outside the DUX4-rearranged cases. Within DUX4-rearranged leukemia, the ERG-deletion was associated with the higher total number of copy-number aberrations, and, importantly, the ERG-deletion positivity by PCR was associated with better outcome (ERG-deletion positive/negative: 5-year EFS 93%/68%, p=0.022; 5-year OS 97%/75%, p=0.029). Ultra-deep amplicon-sequencing revealed distinct coexisting ERG-deletions in 22/24 patients. In conclusion, our data demonstrate inadequate sensitivity of single-nucleotide-polymorphism array for ERG-deletion detection, unacceptable for proper IKZF1plus classification. Even using more sensitive methods (polymerase-chain-reaction/amplicon-sequencing) for its detection, ERG-deletion is absent in 22-34% of DUX4-rearranged leukemia and does not represent adequately sensitive marker of this leukemia subtype. Importantly, the ERG-deletion potentially stratifies the DUX4-rearranged leukemia into biologically/clinically distinct subsets. Frequent polyclonal pattern of ERG-deletions shows that late origin of this lesion is more common than described previously.


Cytogenetics and Molecular Genetics; DUX4; ERG; IKZF1; Pediatric Acute Lymphoblastic Leukemia

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