P53 GENE INACTIVATION IN ACUTE LYMPHOBLASTIC-LEUKEMIA OF B-CELL LINEAGE ASSOCIATES WITH CHROMOSOMAL BREAKPOINTS AT 11Q23 AND 8Q24

The clinical heterogeneity of acute lymphoblastic leukemia (ALL) of B cell lineage reflects the presence of distinct molecular pathways lead ing to well-defined ALL molecular subtypes. These molecular pathways i nclude the formation of the fusion transcripts BCR/ABL and E2A/PBX1, d ue to t(9;22) and t(1;19), respectively, as well as rearrangements of the MLL gene at 11q23 and of c-MYC at 8q24. Hyperdiploid ALL in the ab sence of chromosomal structural abnormalities is an additional ALL mol ecular subtype. Mutations of the RAS family genes and of the p53 tumor suppressor gene represent additional genetic lesions detected in a fr action (10-20%) of ALL cases. RAS activation in ALL may be detected in all molecular subtypes of ALL and denotes poor prognosis. Conversely, little is known regarding the clinical and biological features of ALL cases carrying p53 mutations. In order to help clarify the role of p5 3 inactivation in ALL development, we have determined the frequency of p53 mutations throughout the molecular spectrum of B cell lineage ALL . We report that p53 inactivation in ALL of B cell lineage is restrict ed to cases carrying a rearrangement of MLL or c-MYC, whereas it is co nsistently negative in other molecular subgroups. These data underline the molecular heterogeneity of ALL of B cell lineage and indicate tha t at least some of the molecular pathways involved in ALL pathogenesis require more than one genetic lesion.