INK4 Locus Deletion in Childhood Acute Lymphoblastic Leukemia (ChALL)-a Preliminary Clinical Evaluation

Introduction: Deletions of the INK4 locus (on chromosomal region 9p21) are common in chALL. p16/14 and p15 genes lost with INK4 deletion are tumor suppressors, with a well-documented role in regulating cell cycle and chemosensitivity and in promoting apoptosis in vitro. However, the clinical significance of INK4 deletions remains unclear.

Patients & Methods: The study included 78 children (49 boys and 29 girls) with ALL (medium age: 3,12, range:0,7 to 16,5 ). The disease was of B- and T-cell origin in 70 and 8 cases, respectively. INK4 deletion was investigated by interphase FISH on the diagnostic bone marrow samples and the result was correlated with the patients’ demographic data, biological and clinical parameters, and disease outcome. All patients were treated according to the ALL-BFM-95 protocol and followed-up for 11–105 (medium 41) months.

Results: INK4 locus deletion was found in 24 cases (30.8%). The loss was hemizygous in 15 (19.2%) and homozygous in 9 cases (11.5%). A positive finding was strongly associated with disease of T-cell origin (p=0.008). Apart from a weak correlation between INK4 deletion and advanced age (p=0.068), there was no association with sex, initial leucocytosis level, cytogenetic category, risk group grade according to the ALL-BFM- 95 criteria or the presence of residual disease at days 15 and 33. Nevertheless, INK4 homozygous deletion was significantly associated with disease-free (p=0.004) and overall survival (p=0.002), while the respective associations for an hemizygous deletions were found insignificant (p=0.137 and p=0.131).

Conclusions: The findings from this cohort of children suggest that INK4 homozygous deletion is an unfavorable prognostic factor in chALL, even for cases in which an aggressive course cannot be predicted by the conventional risk estimating criteria. Unclear results with regard to hemizygous deletion may be attributed to the functional state of remaining p16/p14 and p15 genes on the non-deleted chromosome 9. The study of a greater group of patients and the extension of the follow-up period will hopefully clarify whether INK4 deletion is an independent prognostic factor and whether it could be incorporated in risk evaluation guidelines, especially for cases which would otherwise be treated as chALL of standard or medium risk.