Analysis of p53 mutations in a large series of lymphoid hematologic malignancies of childhood

Wada, Makio; Bartram, CR; Nakamura, H; Hachiya, Misao; Chen, D.L.; Borenstein, Jeff; Cw, Miller; Ludwig, Leopold; Hansen-Hagge, TE; Wd, Ludwig

doi:10.1182/blood.v82.10.3163.bloodjournal82103163

Cited by 25 publications

(25 citation statements)

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“…An obvious candidate as regulator is the tumor suppressor p53, which directly transactivates bax upon DNA damage and is also able to downregulate bcl-2 (Miyashita et al, 1994;Miyashita and Reed, 1995). However, in contrast to established cell lines (Findley et al, 1997), p53 mutations are infrequent in primary blasts from childhood ALL (5 out of 312) (Wada et al, 1993).…”

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confidence: 75%

Mutational analysis of Bax and Bcl2 in childhood acute lymphoblastic leukaemia

Salomons¹,

Buitenhuis²,

Muñoz³

et al. 1998

Int. J. Cancer

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In childhood acute lymphoblastic leukaemia there are large interpatient variations in levels of the apoptosis-regulating proteins Bax and Bcl-2, but the molecular basis for this variation is unknown. Point-mutations in bax have been reported in cell lines derived from haematological malignancies. Frameshift mutations, which result in reduced Bax levels, have also been found in colon cancer of the microsatellite mutator phenotype. Bcl-2 overexpression, or gain of function mutations in the open reading frame (ORF) or in the translational repressor, the upstream ORF (uORF) of bcl-2, might also be important in deregulating its function or expression. We have therefore analyzed 21 bone marrow aspirates from untreated childhood acute lymphoblastic leukaemia and 2 from myeloid leukaemia for mutations in bax and bcl-2. DNA sequence analysis of the ORFs of bax and bcl-2 and of the uORF of bcl-2 revealed no mutations, despite the large range in expression levels. Thus, mutations within the (u)ORFs of bax and bcl-2 that (in)activate or deregulate Bax and Bcl-2 are infrequent in primary childhood acute leukaemia and do not play a major role in regulation of the encoded proteins in this disease.

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mentioning

confidence: 75%

Mutational analysis of Bax and Bcl2 in childhood acute lymphoblastic leukaemia

Salomons¹,

Buitenhuis²,

Muñoz³

et al. 1998

Int. J. Cancer

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“…For instance, Gaidano et al (1994) showed that only 60% of CLL cases with p53 mutations had allele loss, assessed by Southern blot using polymorphic probes adjacent to the p53 region, whereas Wattel et al (1994) reported that 75% of mutated CLL had loss of the wild-type sequence at the site of the mutation. Baldini et al (1994) showed that 85% of cases with splenic lymphoma presenting p53 mutations had loss of the remaining allele whereas Wada et al (1993) studied 359 cases of haematological malignancies and found in all but one of the cases with mutations a migrating wild-type band together with the altered band, suggesting that only 22% of these cases with p53 mutation had loss of the remaining p53 allele. In this study there was no evidence of an additional signal corresponding to the normal p53 sequence in four out of five CLL cases with p53 mutations, which indicates a close correlation between p53 mutation and deletion of the remaining allele.…”

Section: Discussionmentioning

confidence: 99%

p53 abnormalities in CLL are associated with excess of prolymphocytes and poor prognosis

et al. 1997

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Summary.To determine the role of the p53 gene in chronic lymphocytic leukaemia (CLL) and its possible involvement in the pathogenesis of a progressive form of CLL characterized by > 10% prolymphocytes (CLL/PL), we selected 32 cases, 17 with typical morphology and 15 CLL/PL. The extent of inactivation of p53 was examined by assessing loss of heterozygosity (LOH) at 17p13.3, by sequencing the highly conserved region (exons 5-9) of the p53 gene and by analysing p53 protein expression. LOH was detected in 8/28 (29%) cases, p53 mutations in 5/32 (16%) cases and p53 expression in 5/27 (19%) cases. Overall 11 cases (30%) had p53 abnormalities of which eight cases had CLL/PL. There was a significant association between CLL/PL and p53 abnormalities (P ¼ 0·05); 75% of cases with LOH, 80% of p53 mutations and 80% of cases positive for p53 protein had CLL/PL. Thus, p53 inactivation is the first gene abnormality identified so far to be involved in the development of CLL/PL.All the cases with typical CLL and p53 abnormalities had only one allele affected whereas 4/6 CLL/PL had both alleles inactivated. This difference in the extent of p53 inactivation suggests that accumulation of p53 abnormalities may be associated with progression of CLL to CLL/PL.CLL cases with p53 abnormalities were characterized by a higher incidence of stage C (P < 0·025), a higher proliferative rate (P ¼ 0·05), short survival (P < 0·005) and resistance to first-line therapy (P < 0·02) but not to nucleoside analogues. Analysis of the correlation between p53 status and incidence of trisomy 12 by fluorescence in situ hybridization (FISH) showed that trisomy 12 was more frequent in cases without p53 abnormalities, suggesting that trisomy 12 and p53 may represent different pathways of transformation in CLL.

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“…The incidence of p53 tumor suppressor gene mutations in newly diagnosed childhood ALL is 2-3% [19,20]. Therefore, it seems unlikely that loss of p53 function plays a role in the pathogenesis of this disease [21].…”

Section: Discussionmentioning

confidence: 99%

Second malignant neoplasms in childhood acute lymphoblastic leukemia: Primitive neuroectodermal tumor of the chest wall with germline p53 mutation as a second malignant neoplasm

et al. 2004

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About 80% of children treated for acute lymphoblastic leukemia (ALL) will be long-term survivors. Second malignant neoplasm (SMNs) are a devastating sequelae observed on these children, with an estimated cumulative risk of 2-3.3% fifteen years after diagnosis. Primitive neuroectodermal tumor of bone (PNET) is rarely observed as a SMN following treatment of childhood ALL. The authors described the occurrence of a chest wall PNET of the bone at the site of a central line placement associated with both germ-line and tumor cell p53 mutation in a 8-year-old boy 1 year after completing therapy for standard risk ALL. A review of the literature of 25,051 children treated for ALL discovered 230 SMNs (0.99%), and only one case of PNET of the bone was noted among this group. The occurrence of a SMN in children treated for ALL is a rare event. Such an occurrence, in particular the development of an unusual SMN, should be evaluated for a germline p53 mutation. Am.

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Analysis of p53 mutations in a large series of lymphoid hematologic malignancies of childhood

Cited by 25 publications

References 0 publications

Mutational analysis of Bax and Bcl2 in childhood acute lymphoblastic leukaemia

Mutational analysis of Bax and Bcl2 in childhood acute lymphoblastic leukaemia

p53 abnormalities in CLL are associated with excess of prolymphocytes and poor prognosis

Second malignant neoplasms in childhood acute lymphoblastic leukemia: Primitive neuroectodermal tumor of the chest wall with germline p53 mutation as a second malignant neoplasm

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