MUTATIONAL ANALYSIS OF BAX AND BCL-2 IN CHILDHOOD ACUTE LYMPHOBLASTIC-LEUKEMIA

In childhood acute lymphoblastic leukaemia there are large interpatien t variations in levels of the apoptosis-regulating proteins Pax and Bc l-2, but the molecular basis for this variation is unknown. Point-muta tions in box have been reported in cell lines derived from haematologi cal malignancies. Frameshift mutations, which result in reduced Pax le vels, have also been found in colon cancer of the microsatellite mutat or phenotype. Bcl-2 overexpression, or gain of function mutations in t he open reading frame (OBF) or in the translational repressor, the ups tream ORF (uORF) of bcl-2, might also be important in deregulating its function or expression. We have therefore analyzed 21 bone marrow asp irates from untreated childhood acute lymphoblastic leukaemia and 2 fr om myeloid leukaemia for mutations in box and bcl-2, DNA sequence anal ysis of the ORFs of box and bcl-2 and of the uORF of bcl-2 revealed no mutations, despite the large range in expression levels. Thus, mutati ons within the (u)ORFs of box and bcl-2 that (in)activate or deregulat e Pax and Bcl-2 are infrequent in primary childhood acute leukaemia an d do not play a major role in regulation of the encoded proteins in th is disease. (C) 1998 Wiley-Liss, Inc.