TY - JOUR
T1 - Analysis of rare driving events in pediatric acute myeloid leukemia
AU - Noort, Sanne
AU - van Oosterwijk, Jolieke
AU - Ma, Jing
AU - Garfinkle, Elizabeth A.R.
AU - Nance, Stephanie
AU - Walsh, Michael
AU - Song, Guangchun
AU - Reinhardt, Dirk
AU - Pigazzi, Martina
AU - Locatelli, Franco
AU - Hasle, Henrik
AU - Abrahamsson, Jonas
AU - Jarosova, Marie
AU - Kelaidi, Charikleia
AU - Polychronopoulou, Sophia
AU - van den Heuvel-Eibrink, Marry M.
AU - Fornerod, Maarten
AU - Gruber, Tanja A.
AU - Zwaan, C. Michel
N1 - Publisher Copyright:
©2023 Ferrata Storti Foundation.
PY - 2023/1
Y1 - 2023/1
N2 - Elucidating genetic aberrations in pediatric acute myeloid leukemia (AML) provides insight in biology and may impact on risk-group stratification and clinical outcome. This study aimed to detect such aberrations in a selected series of samples without known (cyto)genetic aberration using molecular profiling. A cohort of 161 patients was selected from various study groups: DCOG, BFM, SJCRH, NOPHO and AEIOP. Samples were analyzed using RNA sequencing (n=152), whole exome (n=135) and/or whole genome sequencing (n=100). In 70 of 156 patients (45%), of whom RNA sequencing or whole genome sequencing was available, rearrangements were detected, 22 of which were novel; five involving ERG rearrangements and four NPM1 rearrangements. ERG rearrangements showed self-renewal capacity in vitro, and a distinct gene expression pattern. Gene set enrichment analysis of this cluster showed upregulation of gene sets derived from Ewing sarcoma, which was confirmed comparing gene expression profiles of AML and Ewing sarcoma. Furthermore, NPM1-rearranged cases showed cytoplasmic NPM1 localization and revealed HOXA/B gene overexpression, as described for NPM1 mutated cases. Single-gene mutations as identified in adult AML were rare. Patients had a median of 24 coding mutations (range, 7-159). Novel recurrent mutations were detected in UBTF (n=10), a regulator of RNA transcription. In 75% of patients an aberration with a prognostic impact could be detected. Therefore, we suggest these techniques need to become standard of care in diagnostics.
AB - Elucidating genetic aberrations in pediatric acute myeloid leukemia (AML) provides insight in biology and may impact on risk-group stratification and clinical outcome. This study aimed to detect such aberrations in a selected series of samples without known (cyto)genetic aberration using molecular profiling. A cohort of 161 patients was selected from various study groups: DCOG, BFM, SJCRH, NOPHO and AEIOP. Samples were analyzed using RNA sequencing (n=152), whole exome (n=135) and/or whole genome sequencing (n=100). In 70 of 156 patients (45%), of whom RNA sequencing or whole genome sequencing was available, rearrangements were detected, 22 of which were novel; five involving ERG rearrangements and four NPM1 rearrangements. ERG rearrangements showed self-renewal capacity in vitro, and a distinct gene expression pattern. Gene set enrichment analysis of this cluster showed upregulation of gene sets derived from Ewing sarcoma, which was confirmed comparing gene expression profiles of AML and Ewing sarcoma. Furthermore, NPM1-rearranged cases showed cytoplasmic NPM1 localization and revealed HOXA/B gene overexpression, as described for NPM1 mutated cases. Single-gene mutations as identified in adult AML were rare. Patients had a median of 24 coding mutations (range, 7-159). Novel recurrent mutations were detected in UBTF (n=10), a regulator of RNA transcription. In 75% of patients an aberration with a prognostic impact could be detected. Therefore, we suggest these techniques need to become standard of care in diagnostics.
UR - http://www.scopus.com/inward/record.url?scp=85145424430&partnerID=8YFLogxK
U2 - 10.3324/haematol.2021.280250
DO - 10.3324/haematol.2021.280250
M3 - Article
C2 - 35899387
AN - SCOPUS:85145424430
SN - 0390-6078
VL - 108
SP - 48
EP - 60
JO - Haematologica
JF - Haematologica
IS - 1
ER -