Analysis of the cyclin-dependent kinase inhibitors p18 and p19 in mantle-cell lymphoma and chronic lymphocytic leukemia

Background: Mantle-cell lymphoma (MCL) is characterized by overexpression of the G1 cyclin, cyclin D1, strongly implicating this cell-cycle regulatory element in MCL pathogenesis. Recently, loss-of-function mutations in cell-cycle negative regulatory elements, including p53 point mutations and deletions of the cyclin-dependent kinase inhibitors (CDKI) p15 and p16 have been described in a subset of MCLs and have been associated with aggressive clinical course, blastic morphology, and extranodal dissemination. The objective of the present study was to analyze two newly identified members of the p16 (INK4A; MTS1) CDKI family, p18 and p19, in MCL. Such analyses have not been previously reported. Patients and methods. DNA was isolated from tissue biopsies, peripheral blood cells, or bone marrow cells of 45 patients with MCL and 15 with chronic lymphocytic leukemia (CLL). Southern blot analysis was performed with pig and p19 probes and compared to placental control DNA and to control probe hybridizations for evidence of pls or p19 gene deletion or rearrangement. Results: P18 deletion was identified in one MCL but in no case of CLL. One MCL sample had rearrangement of the p18 gene; this case also had coexisting homozygous p15 and p16 deletion. Both cases with p18 abnormalities had blastic morphology, and one had extranodal disease with renal parenchymal invasion. Conclusions: Pls rearrangement or deletion as detected by Southern blot is a rare event in MCL, but may be associated with blastic morphology. P53 mutations and deletions of the CDKI p15 and p16 appear to be more frequent in MCL, although further studies are necessary to assess the presence of inactivating point mutations or altered expression of p16 family proteins.