The prognostic significance of p16(INK4a)/p14(ARF) and p15(INK4b) deletions in adult acute lymphoblastic leukemia

Cytogenetic/molecular abnormalities significantly influence the prognosis of patients with acute leukemia. Recently, two genes, p16(INK4a) and p15(INK4b), encoding two cyclin-dependent kinase inhibitor proteins of the INK4 family of M(r) 15,000 and 16,000, respectively, have been localized to 9p21. Remarkably, the p16(INK4a) locus has been found to encode a second protein, p14(ARF), known as p19(ARF) in mice, with a distinct reading frame. Like p16(INK4a), p14(ARF) is involved in cell cycle regulation, blocking cells at the G₁ restriction point through the activity of MDM-2 and p53. We studied bone marrow samples of 42 newly diagnosed and untreated patients with acute lymphoblastic leukemia for the incidence of deletions of p16(INK4a/p14(ARF) and p15(INK4b) using Southern blot analysis and determined the clinical outcome with regard to complete remission (CR) duration, event- free survival, and overall survival. We found deletions of p16(INK4a)/p14(ARF) in 17 of 42 patients (40%), with homozygous deletions in 11 of 42 patients (26%) and hemizygous deletions in 6 of 42 patients (14%). The gene for p15(INK4b) was codeleted in most, but not all, cases and was never deleted without deletion of p16(INK4a)/p14(ARF). NO correlation was observed between molecular studies and karyotype abnormalities as determined by conventional cytogenetics. Furthermore, no difference was found in the CR rate, CR duration, event-free survival, and overall survival in patients with homozygous gene deletions compared to patients with no deletions or loss of only one allele.