Involvement of the ALL-1 gene in a solid tumor.

Translocations involving chromosome band 11q23, found in 5-10% of human acute leukemias, disrupt the ALL-1 gene. This gene is fused by reciprocal translocation with a variety of other genes in acute lymphoblastic and myelogenous leukemias, and it undergoes self-fusion in acute myeloid leukemias with normal karyotype or trisomy 11. Here we report an alteration of the ALL-1 gene in a gastric carcinoma cell line (Mgc80-3). Characterization of this rearrangement revealed a three-way complex translocation, involving chromosomes 1 and 11, resulting in a partial duplication of the ALL-1 gene. Sequencing of reverse transcription-PCR products and Northern blot analysis showed that only the partially duplicated ALL-1 gene was transcribed, producing an mRNA with exon 8 fused to exon 2. This report of ALL-1 gene rearrangement in a solid tumor suggests that ALL-1 plays a role in the pathogenesis of some solid malignancies. The absence of the normal transcript in this cell line, in association with the loss-of-heterozygosity studies on chromosome 11q23 seen in solid tumors, suggests that ALL-1 is involved in tumorigenesis by a loss-of-function mechanism.

Wild-type p53 protein undergoes cytoplasmic sequestration in undifferentiated neuroblastomas but not in differentiated tumors.

Neuroblastoma (NB), a tumor arising from the sympathetic nervous system, is one of the most common malignancies in childhood. Several recent reports on the p53 genotype found virtually exclusive wild-type status in primary tumors, and it was postulated that p53 plays no role in the development of NB. Here, however, we report that the vast majority of undifferentiated NBs exhibit abnormal cytoplasmic sequestration of wild-type p53. This inability of p53 to translocate to the nucleus presumably prevents the protein from functioning as a suppressor. Thirty of 31 cases (96%) of undifferentiated NB showed elevated levels of wild-type p53 in the cytoplasm of all tumor cells concomittant with a lack of nuclear staining. p53 immunoprecipitation from tumor tissues showed a 4.5- to 8-fold increase over normal protein levels. All of 10 tumors analyzed harbored wild-type p53 by direct sequencing of full-length cDNA and Southern blot. In addition, no MDM-2 gene amplification was seen in all 11 tumors analyzed. In contrast, no p53 abnormality was detected in 14 differentiated ganglioneuroblastomas and 1 benign ganglioneuroma. We conclude that loss of p53 function seems to play a major role in the tumorigenesis of undifferentiated NB. This tumor might abrogate the transactivating function of p53 by inhibiting its access to the nucleus, rather than by gene mutation. Importantly, our results suggest that (i) this could be a general mechanism for p53 inactivation not limited to breast cancer (where we first described it) and that (ii) it is found in a tumor previously not thought to be affected by p53 alteration.