Small sizes and indolent evolutionary dynamics challenge the potential role of P2RY8-CRLF2-harboring clones as main relapse-driving force in childhood ALL

The P2RY8-CRLF2 fusion defines a particular relapse-prone subset of childhood ALL in AIEOP-BFM 2000 protocols.

To investigate whether and to what extent different clone sizes influence disease and relapse development, we quantified the genomic P2RY8-CRLF2 fusion product and correlated it with the corresponding CRLF2 expression levels in patients enrolled in the BFM-ALL 2000 protocol in Austria.

Of 268 cases without recurrent chromosomal translocations and high-hyperdiploidy, representing approximately 50% of all cases, 67 (25%) were P2RY8-CRLF2-positive. The respective clone sizes were =20% in 27% and <20% in 73% of them. The cumulative incidence of relapse of the entire fusion-positive group was clone size independent and significantly higher than that of the fusion-negative one (35±8% vs. 13±3%, P=0.008) and primarily confined to the non-high-risk group.
Of 22 P2RY8-CRLF2-positive diagnosis/relapse pairs, only 4/8 had the fusion-positive dominant clone conserved at relapse, whereas none of the original 14 fusion-positive small clones reappeared as the dominant relapse clone.

Conclusion:
We conclude that the majority of P2RY8-CRLF2-positive clones are small at diagnosis and virtually never generate a dominant relapse clone. Our findings therefore suggest that P2RY8-CRLF2-positive clones do not have the necessary proliferative or selective advantage to evolve into a disease-relevant relapse clone.

Published in the Blood Journal. Read the full article Small sizes and Indolent evolutionary dynamics challenge the role of P2RY8-CRLF2.

Authors / corresponding author*

*Maria Morak,1; Andishe Attarbaschi,2; Susanna Fischer,1; Christine Nassimbeni,1; Reinhard Grausenburger,1; Stephan Bastelberger,1; Stefanie Krentz,3; Gunnar Cario,4; David Kasper,5; Klaus Schmitt,6; Lisa J. Russell,7; Ulrike Pötschger,1; Martin Stanulla,4; Conny Eckert,3; Georg Mann,2; Oskar A. Haas,1,2; Renate Panzer-Grümayer1,2

1 Children’s Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria
2 St. Anna Kinderspital, Medical University Vienna, Vienna, Austria
3 Department of Pediatrics, Division of Oncology and Hematology, Charite´ -Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
4  Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
5 Department of Pediatric and Adolescent Medicine, Medical University Vienna, Vienna, Austria
6 Children’s Hospital, Linz, Austria
7 Leukemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom

 

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