Molecular characterization of acute lymphoblastic leukemia with high CRLF2 gene expression in childhood

Pediatr Blood Cancer. 2017 Oct;64(10). doi: 10.1002/pbc.26539. Epub 2017 Apr 1.

Abstract

Background: A high-level expression of the CRLF2 gene is frequent in precursor B-cell acute lymphoblastic leukemia (pB-ALL) and can be caused by different genetic aberrations. The presence of the most frequent alteration, the P2RY8/CRLF2 fusion, was shown to be associated with a high relapse incidence in children treated according to ALL-Berlin-Frankfurt-Münster (BFM) protocols, which is poorly understood. Moreover, the frequency of other alterations has not been systematically analyzed yet.

Procedure: CRLF2 mRNA expression and potential genetic aberrations causing a CRLF2 high expression were prospectively assessed in 1,105 patients treated according to the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP)-BFM ALL 2009 protocol. Additionally, we determined copy number alterations in selected B-cell differentiation genes for all CRLF2 high-expressing pB-ALL cases, as well as JAK2 and CRLF2 mutations.

Results: A CRLF2 high expression was detected in 26/178 (15%) T-cell acute lymphoblastic leukemia (T-ALL) cases, 21 of them (81%) had been stratified as high-risk patients by treatment response. In pB-ALL, a CRLF2 high expression was determined in 91/927 (10%) cases; the P2RY8/CRLF2 rearrangement in 44/91 (48%) of them, supernumerary copies of CRLF2 in 18/91 (20%), and, notably, the IGH/CRLF2 translocation was detected in 16/91 (18%). Remarkably, 7 of 16 (44%) patients with IGH/CRLF2 translocation had already relapsed. P2RY8/CRLF2- and IGH/CRLF2-positive samples (70 and 94%, respectively) were characterized by a high frequency of additional deletions in B-cell differentiation genes such as IKZF1 or PAX5.

Conclusion: Our data suggest that this high frequency of genetic aberrations in the context of a high CRLF2 expression could contribute to the high risk of relapse in P2RY8/CRLF2- and IGH/CRLF2-positive ALL.

Keywords: CRLF2; IGH/CRLF2; P2RY8/CRLF2; acute lymphoblastic leukemia; prognosis.

Publication types

  • Clinical Trial
  • Multicenter Study

MeSH terms

  • Adolescent
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Asparaginase / administration & dosage
  • Child
  • Child, Preschool
  • Daunorubicin / administration & dosage
  • Female
  • Gene Expression Regulation, Leukemic / drug effects*
  • Gene Rearrangement
  • Humans
  • Ikaros Transcription Factor / biosynthesis
  • Ikaros Transcription Factor / genetics
  • Infant
  • Male
  • Oncogene Proteins, Fusion / biosynthesis
  • Oncogene Proteins, Fusion / genetics
  • PAX5 Transcription Factor / biosynthesis
  • PAX5 Transcription Factor / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Prednisone / administration & dosage
  • Receptors, Cytokine / biosynthesis*
  • Receptors, Cytokine / genetics
  • Receptors, Purinergic P2Y / biosynthesis
  • Receptors, Purinergic P2Y / genetics
  • Vincristine / administration & dosage

Substances

  • CRLF2 protein, human
  • IKZF1 protein, human
  • Oncogene Proteins, Fusion
  • P2RY8 protein, human
  • PAX5 Transcription Factor
  • PAX5 protein, human
  • Receptors, Cytokine
  • Receptors, Purinergic P2Y
  • Ikaros Transcription Factor
  • Vincristine
  • Asparaginase
  • Prednisone
  • Daunorubicin

Supplementary concepts

  • PVDA protocol