IGH@ Translocations, CRLF2 Deregulation and Microdeletions in Adolescents and Adults with Acute Lymphoblastic Leukemia (2012)

Author(s): Moorman AV, Schwab C, Ensor HM, Russell LJ, Morrison H, Jones L, Masic D, Patel B, Rowe JM, Tallman M, Goldstone AH, Fielding AK, Harrison CJ

    Abstract: 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/Methods The cohort comprised 454 patients (15-60 years old) treated on UKALLXII/ECOG2993 with Philadelphia-negative B-cell precursor ALL. Fluorescence in situ hybridisation (FISH) and Multiplex Ligation-dependent Probe Amplification (MLPA) were used to detect these genetic alterations. Results Twenty (5%) patients had CRLF2-d [P2RY8-CRLF2 (n=7), IGH@-CRLF2 (n=13)] while 36 (8%) patients harboured 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 101/304 (33%) cases harbouring one and 102 (33%) two or more alterations, occurring with varying frequency in all cytogenetic subgroups. The 5 year event-free, relapse-free (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 to other patients (30%), whereas those with IGH@-t or IKZF1 deletions had a lower OS (27% and 35%). 4 Conclusions 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.

    • Type of Article: Original Research
    • Alternate Journal: J Clin Oncol.
    • Date: 30-06-2012
    • Journal: Journal of Clinical Oncology
    • Volume: 30
    • Issue: 25
    • Pages: 3100-3108
    • Publisher: American Society of Clinical Oncology
    • Publication type: Article
    • Bibliographic status: Published

    Keywords: acute lymphoblastic leukaemia, prognosis, adult, genetics, IGH@ translocations, CRLF2 deregulation, IKZF1 deletions, PAX5 alterations


    Professor Christine Harrison

    Professor Anthony Moorman
    Professor of Genetic Epidemiology

    Dr Lisa Russell
    Newcastle University Research Fellow