Shortened survival after relapse in T-cell acute lymphoblastic leukemia patients with p16/p15 deletions

Diccianni, Mitchell B.; Batova, Ayse; Yu, John; Vu, Tien P.; Pullen, Jeanette; Amylon, Michael D.; Pollock, Bradley H; Yu, Alice L.

doi:10.1016/s0145-2126(97)00007-6

Cited by 30 publications

(34 citation statements)

References 25 publications

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“…Six studies on children with ALL have been reported, two of which described a worse prognosis of patients with p16 del (and p15 del ) 45,106 ; four other series did not detect any statistically significant difference between these patients. 34,35,48,54,55 In adults, one study on ALL failed to document any prognostic value for p16 deletion. 57 Two further studies on ATL and B-NHL described a worse prognosis for adults with p15 del /p16 del than for cases in the p15 wt /p16 wt groups.…”

Section: Prognostic Relevance Of P15 and P16 Alterationsmentioning

confidence: 99%

“…Two large studies on children with BCP-ALL and T-ALL detected the same frequency of p15 del /p16 del and p15 met /p16 met when comparing cohorts of children at diagnosis with patients at relapse. 35,48,61 In adults, higher frequencies of p16 deletion were published for patients with aggressive or high-grade B-NHL vs cases with indolent or low-grade variants of these disorders. 66,79 Definitely fewer patients were examined in the paired sequential analysis encompassing children with BCP-ALL, T-ALL and CML and adults with ALL, mature T and B cell lymphoid disorders and MDS (Table 5).…”

Section: Tablementioning

confidence: 99%

“…26 In most cases (greater than two-thirds of the patients) with p16 deletions, its homologous neighbor p15 is also altered; however, the overall higher incidence of p16 deletions over p15 is consistent with the notion that p16 rather than p15 is the target of the deletion on 9p21 in leukemia-lymphoma. [33][34][35] The detailed analysis over the last 3-4 years on the inactivation of these genes in large panels of primary cells and the increasing use of continuous leukemia-lymphoma cell lines with alterations of INK4 genes has prompted this review. While some data on p18 and p19 have been reported, the bulk of information concerns p15 and p16.…”

Section: Introductionmentioning

confidence: 99%

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Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia–lymphoma cells

1998

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The cyclin-dependent kinase inhibitors known as p15, p16, p18 and p19 have been suggested as candidates for tumor suppressor genes. The main genetic alterations are deletions (bior monoallelic) or 5Ј CpG island methylation of p15 and p16; very few cases or cell lines had p18 or p19 deletions or hypermethylation. Hypermethylation and homozygous deletions of tumor suppressor genes establish a new paradigm of inactivation by lack of expression, in contrast to the previously identified tumor suppressors which are predominantly inactivated by point mutations followed by loss of the wild-type allele. Here, the literature data on alterations of this gene family in more than 4700 primary cases of leukemia or lymphoma and some 320 continuous leukemia-lymphoma cell lines are summarized. Among hematopoietic malignancies, the highest frequencies of p15 del and p16 del were seen in acute lymphoblastic leukemia (ALL) (Ͼ30%) with striking rates in T-ALL (Ͼ50%), but also high rates in B cell precursor (BCP)-ALL (Ͼ20%); the rates of deletions in chronic lymphoid leukemia (CLL), multiple myeloma, acute and chronic myeloid leukemia (AML and CML), and myelodysplastic syndromes (MDS) were rather low, only some B cell and T cell lymphomas showed increased frequencies. Results are quite different with regard to the second mode of inactivation, hypermethylation of the promoter region. Here, p15 is most often inactivated, at particularly high frequencies in the disorders lacking any p15/p16 deletions: 40-80% p15 met in AML, MDS and multiple myeloma. Also p15 met rates in BCPand T-ALL cases were high (c. 40%). There is controversy concerning the prognostic impact of p15 and p16 aberrations with some studies describing a significant correlation between inactivation of these genes and poor prognosis, while most others did not detect any prognostic relevance, at least in pediatric ALL; there may be a worse prognosis for adults with B or T cell lymphomas. Despite the small number of cases studied, paired sequential analyses suggested that disease progression is associated with loss of p15/p16 activity in a certain percentage of adult patients. p15 del /p16 del and p15 met /p16 met were also detected in the large panel of leukemia-lymphoma cell lines studied. In general, the results in cell lines reproduce the data seen in primary cells with the important difference that the rates of p15/p16 inactivation are clearly higher in the cultured cells compared with the freshly explanted cells. Retrovirus-or electroporation-mediated ectopic gene transfer of p16 wild-type into p16-deficient cell lines led to growth inhibition, arrest in G 1 (without apoptosis) and occasionally to differentiation, suggesting that the malignant phenotype of p16 −/− cell lines can, at least partially, be reversed by restoring p16 gene expression. A striking inverse correlation between the absence of p16 (due to deletion) and presence of wild-type retinoblastoma gene was observed in cell lines confirming a common growth suppressor pathway; no comparable relationship of p1...

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Section: Prognostic Relevance Of P15 and P16 Alterationsmentioning

confidence: 99%

Section: Tablementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia–lymphoma cells

1998

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“…9 Some authors have suggested that alterations in the p16 gene are associated with a higher frequency of relapse and lower survival in T-cell acute lymphoblastic leukemias both in adults 10 and children. [11][12][13] Therefore, p16 inactivation might be of prognostic value in acute lymphoblastic leukemias, especially T-cell acute lymphoblastic leukemias, playing an important role in its genesis or evolution. 6,11,[14][15][16][17][18][19][20][21][22][23][24] The most frequent alterations in the p16 gene are total or partial homozygous deletions.…”

Section: Introductionmentioning

confidence: 99%

“…However, the reported frequency of these mutations is highly variable, ranging from 0 to 100% depending on the origin of the patient. 12,17,18,[23][24][25][26][27][28][29][30][31] In acute lymphoblastic leukemias, the frequency of nucleotide substitutions in the p16 gene is estimated to be approximately 8%, ranging from 0 to 5% for B-cell acute lymphoblastic leukemias and from 0 to 13% for T-cell acute lymphoblastic leukemias. 12,16,18,19,25,28,29 Based on the importance of the p16 gene in acute lymphoblastic leukemias, especially T-cell acute lymphoblastic leukemias, the aim of the present study was to determine probable alterations in the p16 gene in Brazilian children with acute lymphoblastic leukemias using the polymerase chain reaction-single stranded conformation polymorphism (PCR-SSCP) method and direct DNA sequencing and also to compare the event-free survival (EFS) using the Kaplan-Meier method and the log-rank test for patients carrying normal or altered p16 genes.…”

Section: Introductionmentioning

confidence: 99%

Analysis of p16 gene mutations and deletions in childhood acute lymphoblastic leukemias

et al. 2003

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PARTICIPANTS:Fifty-six children with ALL (mean age 4 years). Forty (71.43%) had B-cell and 12 (21.43%) had T-cell ALL; 4 (7.1%) were biphenotypic.SAMPLE: DNA samples were extracted from bone marrow upon diagnosis and/or relapse. In 2 T-cell cases, DNA from cerebrospinal fluid (CSF) was analyzed. MAIN MEASUREMENTS:Deletions or nucleotide substitutions in exons 1, 2 and 3 of the p16 gene were determined by PCR and nucleotide sequencing. Event-free survival was determined by the Kaplan-Meyer and log-rank test for patients carrying normal and altered p16. RESULTS:Deletions in exon 3 were observed in five cases. Abnormal migration in PCR was observed in seven cases for exon 1, six for exon 2, and five for exon 3. Mutations in exon 1 were confirmed by direct DNA sequencing in four cases and in exon 2 in two cases. The Kaplan-Meyer survival curves and the log-rank test showed no significant differences in 5-year EFS between children with normal or altered p16, or between patients with B-ALL carrying normal or altered p16 gene. Patients with T-ALL could not be evaluated via Kaplan-Meier due to the small number of cases. CONCLUSIONS:Our results, particularly regarding deletion frequency, agree with others suggesting that deletions in the p16 are initial events in leukemia genesis. The small number of samples did not allow stablishment of correlation between childhood ALL and the p16 point mutations found in our study. Kaplan-Meier analysis revealed no significant correlation between EFS and alterations in ALL. The p16 alterations frequency observed for B and T-ALL agreed with reports from other centers.

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Frequent deregulation ofp16 and thep16/G1 cell cycle-regulatory pathway in neuroblastoma

et al. 1999

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Alterations of the p16 gene in neuroblastoma are very rare. Pronounced expression of p16 at both the transcript and protein levels, however, was observed in 7 of 19 (39%) neuroblastoma cell lines and 2 of 6 (33%) primary neuroblastoma samples. As p16 expression is tightly controlled in a feedback loop with Rb, we investigated the possibility that changes in p16 expression were reflective of alterations of the downstream components in the G1 regulatory pathway. Two cell lines and one primary sample highly expressing p16 were shown to harbor CDK4 amplification. The cyclin D2 gene was infrequently expressed in neuroblastoma cell lines and did not correlate with p16 expression. Slight variations in the expression of CDK6, cyclins D1, D3 and E; and E2F1 and E2F2 among the cell lines were observed, without apparent correlation with p16 status. No mutations to the p16‐binding site of CDK4 and CDK6 nor any mutations to the coding region of p16 itself were identified in neuroblastoma cell lines. Despite frequent N‐myc amplification in these cell lines, no relationship with this gene was observed either. All cell lines contained Rb protein with varying degrees of phosphorylation, which bears no correlation with p16 expression. Overall, alterations of the G1 pathway in neuroblastoma included relatively frequent p16 expression and infrequent CDK4 amplification and cyclin D2 expression. Despite a reported feedback relationship between p16 expression and Rb/G1 deregulation, p16 expression in neuroblastoma cell lines is independent of Rb gene and phosphorylation status and, in contrast to other cell lines where expression of p16 leads to G1/S arrest, neuroblastoma cell lines proliferate in the presence of elevated levels of p16. Int. J. Cancer 80:145–154, 1999. © 1999 Wiley‐Liss, Inc.

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Shortened survival after relapse in T-cell acute lymphoblastic leukemia patients with p16/p15 deletions

Cited by 30 publications

References 25 publications

Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia–lymphoma cells

Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia–lymphoma cells

Analysis of p16 gene mutations and deletions in childhood acute lymphoblastic leukemias

Frequent deregulation ofp16 and thep16/G1 cell cycle-regulatory pathway in neuroblastoma

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