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

Blood. 2012 Dec 20;120(26):5134-42. doi: 10.1182/blood-2012-07-443218. Epub 2012 Oct 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Cell Size
  • Child
  • Child, Preschool
  • Clonal Evolution / genetics
  • Clonal Evolution / physiology*
  • Clone Cells / pathology
  • Cohort Studies
  • Disease Progression
  • Female
  • Gene Expression Regulation, Leukemic / physiology
  • Humans
  • Infant
  • Male
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism
  • Oncogene Proteins, Fusion / physiology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology*
  • Receptors, Cytokine / genetics
  • Receptors, Cytokine / metabolism
  • Receptors, Cytokine / physiology*
  • Receptors, Purinergic P2Y / genetics
  • Receptors, Purinergic P2Y / metabolism
  • Receptors, Purinergic P2Y / physiology*
  • Recurrence
  • Time Factors

Substances

  • CRLF2 protein, human
  • Oncogene Proteins, Fusion
  • P2RY8 protein, human
  • Receptors, Cytokine
  • Receptors, Purinergic P2Y