Format

Send to

Choose Destination
Leukemia. 2017 Jul;31(7):1491-1501. doi: 10.1038/leu.2016.365. Epub 2016 Nov 30.

Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia.

Author information

1
Children's Cancer Research Institute (CCRI), Leukemia Biology Group, Vienna, Austria.
2
Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany.
3
Department of Pediatrics, Medical University of Schleswig Holstein, Kiel, Germany.
4
Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
5
St Anna Kinderspital, Medical University Vienna, Vienna, Austria.
6
Research Center for Molecular Medicine (CeMM), Vienna, Austria.
7
UFR de Médecine Paris-Diderot, INSERM UMR_S1131-Institute Universitaire d'hématologie, Département de Génétique-UF de Génétique Moléculaire, Hôpital Robert Debré, Paris, France.

Abstract

Children with P2RY8-CRLF2-positive acute lymphoblastic leukemia have an increased relapse risk. Their mutational and transcriptional landscape, as well as the respective patterns at relapse remain largely elusive. We, therefore, performed an integrated analysis of whole-exome and RNA sequencing in 41 major clone fusion-positive cases including 19 matched diagnosis/relapse pairs. We detected a variety of frequently subclonal and highly instable JAK/STAT but also RTK/Ras pathway-activating mutations in 76% of cases at diagnosis and virtually all relapses. Unlike P2RY8-CRLF2 that was lost in 32% of relapses, all other genomic alterations affecting lymphoid development (58%) and cell cycle (39%) remained stable. Only IKZF1 alterations predominated in relapsing cases (P=0.001) and increased from initially 36 to 58% in matched cases. IKZF1's critical role is further corroborated by its specific transcriptional signature comprising stem cell features with signs of impaired lymphoid differentiation, enhanced focal adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug resistance. Our findings support the notion that P2RY8-CRLF2 is dispensable for relapse development and instead highlight the prominent rank of IKZF1 for relapse development by mediating self-renewal and homing to the bone marrow niche. Consequently, reverting aberrant IKAROS signaling or its disparate programs emerges as an attractive potential treatment option in these leukemias.

PMID:
27899802
PMCID:
PMC5508072
DOI:
10.1038/leu.2016.365
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center