IGH@ translocations, CRLF2 deregulation, and microdeletions in adolescents and adults with acute lymphoblastic leukemia

J Clin Oncol. 2012 Sep 1;30(25):3100-8. doi: 10.1200/JCO.2011.40.3907. Epub 2012 Jul 30.


Purpose: To determine the prevalence and prognostic impact of significant acute lymphoblastic leukemia (ALL) -related genes: CRLF2 deregulation (CRLF2-d), IGH@ translocations (IGH@-t), and deletions of CDKN2A/B, IKZF1, PAX5, ETV6, RB1, BTG1, and EBF1 in adolescents and adults.

Patients and methods: The cohort comprised 454 patients (age 15 to 60 years old) treated on the multicenter United Kingdom Acute Lymphoblastic Leukaemia Trial XII/Eastern Cooperative Oncology Group 2993 trial (UKALLXII/ECOG2993) with Philadelphia-negative B-cell precursor ALL. Fluorescent in situ hybridization and multiplex ligation-dependent probe amplification were used to detect these genetic alterations.

Results: Twenty patients (5%) had CRLF2-d (P2RY8-CRLF2, n = 7; IGH@-CRLF2, n = 13), and 36 patients (8%) harbored an IGH@-t with a different partner gene. There was little overlap between IGH@-t, CRLF2-d, and established chromosomal abnormalities. Deletions of CDKN2A/B, IKZF1, PAX5, ETV6, RB1, BTG1, or EBF1 were prevalent with 101 (33%) of 304 patients harboring one and 102 (33%) harboring two or more alterations, occurring with varying frequency in all cytogenetic subgroups. The 5-year event-free survival, relapse-free survival (RFS), and overall survival (OS) rates for the whole cohort were 40%, 55%, and 43%, respectively. Patients with CRLF2-d, IGH@-t, and IKZF1 deletions were associated with an inferior outcome in univariate but not multivariate analysis. In particular, CRLF2-d patients had a lower RFS compared with other patients (30%), whereas those with IGH@-t or IKZF1 deletions had a lower OS (27% and 35%, respectively).

Conclusion: CRLF2-d and IGH@-t represent distinct subtypes of adolescent and adult ALL. Deletions of key B-cell differentiation and cell cycle control genes are highly prevalent but vary in frequency by cytogenetic subgroup. CRLF2-d, IGH@-t, and IKZF1 deletions are associated with poor outcome in adolescent and adult ALL.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Chi-Square Distribution
  • Disease Progression
  • Disease-Free Survival
  • Female
  • Gene Deletion*
  • Genetic Predisposition to Disease
  • Humans
  • Ikaros Transcription Factor / genetics
  • Immunoglobulin Heavy Chains / genetics*
  • In Situ Hybridization, Fluorescence
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Multiplex Polymerase Chain Reaction
  • Multivariate Analysis
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / mortality
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / therapy
  • Proportional Hazards Models
  • Receptors, Cytokine / genetics*
  • Risk Assessment
  • Risk Factors
  • Time Factors
  • Translocation, Genetic*
  • Treatment Outcome
  • United Kingdom
  • Young Adult


  • CRLF2 protein, human
  • IKZF1 protein, human
  • Immunoglobulin Heavy Chains
  • Receptors, Cytokine
  • Ikaros Transcription Factor