title: Small sizes and indolent evolutionary dynamics challenge the potential role of P2RY8-CRLF2-harboring clones as main relapse-driving force in childhood ALL.
abstract: 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.
authors.affiliation: Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Maria
authors.initials: M
authors.lastname: Morak
authors.forename: Andishe
authors.initials: A
authors.lastname: Attarbaschi
authors.forename: Susanna
authors.initials: S
authors.lastname: Fischer
authors.forename: Christine
authors.initials: C
authors.lastname: Nassimbeni
authors.forename: Reinhard
authors.initials: R
authors.lastname: Grausenburger
authors.forename: Stephan
authors.initials: S
authors.lastname: Bastelberger
authors.forename: Stefanie
authors.initials: S
authors.lastname: Krentz
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cario
authors.forename: David
authors.initials: D
authors.lastname: Kasper
authors.forename: Klaus
authors.initials: K
authors.lastname: Schmitt
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Russell
authors.forename: Ulrike
authors.initials: U
authors.lastname: Pötschger
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.forename: Conny
authors.initials: C
authors.lastname: Eckert
authors.forename: Georg
authors.initials: G
authors.lastname: Mann
authors.forename: Oskar A
authors.initials: OA
authors.lastname: Haas
authors.forename: Renate
authors.initials: R
authors.lastname: Panzer-Grümayer
mesh_terms: D000293:Adolescent; D048429:Cell Size; D002648:Child; D002675:Child, Preschool; D060965:Clonal Evolution / Q000235:genetics / Q000502:physiology*; D002999:Clone Cells / Q000473:pathology; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology; D006801:Humans; D007223:Infant; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology*; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D058470:Receptors, Purinergic P2Y / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012008:Recurrence; D013997:Time Factors
chemical_list: C498762:CRLF2 protein, human; D015514:Oncogene Proteins, Fusion; C578279:P2RY8 protein, human; D018121:Receptors, Cytokine; D058470:Receptors, Purinergic P2Y