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

Maria Morak, Andishe Attarbaschi, Susanna Fischer, Christine Nassimbeni, Reinhard Grausenburger, Stephan Bastelberger, Stefanie Krentz, Gunnar Cario, David Kasper, Klaus Schmitt, Lisa J. Russell, Ulrike Pötschger, Martin Stanulla, Conny Eckert, Georg Mann, Oskar A. Haas and Renate Panzer-Grümayer
This article has an Erratum 122(7):1328


The P2RY8-CRLF2 fusion defines a particular relapse-prone subset of childhood acute lymphoblastic leukemia (ALL) in Italian Association of Pediatric Hematology and Oncology Berlin-Frankfurt-Münster (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 group (35% ± 8% vs 13% ± 3%, P = .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. 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.

  • Submitted July 13, 2012.
  • Accepted October 17, 2012.
View Full Text