The Prognostic Significance of p16/p14 and p15 Deletions in Adult Acute Lymphoblastic Leukemia

Cytogenetic/molecular abnormalities significantly influence the prognosis of patients with acute leukemia. Recently, two genes, p16 and p15, encoding two cyclin-dependent kinase inhibitor proteins of the INK4 family of Mr 15,000 and 16,000, respectively, have been localized to 9p21. Remarkably, the p16 locus has been found to encode a second protein, p14, known as p19 in mice, with a distinct reading frame. Like p16, p14 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/p14 and p15 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/p14 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 was codeleted in most, but not all, cases and was never deleted without deletion of p16/ p14. 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. INTRODUCTION ALLs result from clonal proliferation, accumulation, and tissue infiltration of neoplastic hematopoietic cells. Disruptions of the molecular mechanisms facilitating normal cell growth and differentiation frequently result from alterations of cell cycle control (1). Transitions of the eukaryotic cell cycle from G1 phase through DNA replication (S phase), G2, and cell division (M phase) are tightly regulated at multiple checkpoints known as restriction points. Progression through these stages is mediated by sequential accumulation of a family of serine-threonine protein kinases called CDKs and cyclins that activate the kinases (2–4). The CDKs are opposed by CDKIs that function like brakes in the cell cycle machinery, assuring the cells’ functional integrity and readiness to progress across cell cycle restriction points, thus preventing uninhibited growth and proliferation