INVOLVEMENT OF THE CYCLIN-DEPENDENT KINASE-4 INHIBITOR (CDKN2) GENE IN THE PATHOGENESIS OF LYMPHOID BLAST CRISIS OF CHRONIC MYELOGENOUS LEUKEMIA

Recent data suggest that homozygous deletion of the cyclin-dependent k inase 4 inhibitor gene (CDKN2), a putative tumour suppressor gene loca ted on chromosome 9p21, represents a common genetic event in human can cer. As the molecular basis of the evolution of chronic myelogenous le ukaemia (CML) into blast crisis remains largely unknown, we decided to investigate if the occurrence of similar deletions could represent on e of the mechanisms underlying the disease progression, Whereas none o f 22 chronic phase CML cases examined showed alterations, we found tha t 3/17 total blast crisis examined (18%) showed a homozygous deletion of the CDKN2 gene. The deletions were restricted to cases of lymphoid blast crisis, being present in 3/8 (40%) of the lymphoid and in none o f the nine myeloid cases examined, The fact that the chronic phase DNA obtained at diagnosis in one of the cases lacks the homozygous deleti on observed in blast crisis, suggests that the final deletion event to ok place concomitantly with the progression of the disease. Furthermor e, the analysis of polymorphic regions on chromosome 9p21 flanking at both sides the CDKN2 gene, showed that deletions at 9p21 differ betwee n cases and are characterized by a wide range of extensions. A concomi tant search for a possible involvement of the p53 tumour suppressor ge ne in the same series of patients showed mutations of the gene and los s of heterozygosity at 17p only in myeloid blast crisis, suggesting th e presence of distinct molecular pathways in the pathogenesis of lymph oid and myeloid blast crisis.