Prognostic importance of p15INK4B and p16INK4 gene inactivation in childhood acute lymphocytic leukemia.

Heyman, Mats; Rasool, Omid; Brandter, L. B.; Liu, Y; Grandér, Dan; Söderhäll, Stefan; Gustavsson, G; Einhorn, S.

doi:10.1200/jco.1996.14.5.1512

Cited by 72 publications

(76 citation statements)

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“…However, the presence of the recently described p19 ARF exon 1 close to the p15 INK4b exons (Larsen et al, 1996) may suggest that p19 ARF , instead of the p15 INK4b gene, is the actual target for these alterations. In fact, the exclusive p15 INK4b gene deletions in ALL have been shown to include the E1b exon of p19 ARF (Heyman et al, 1996). In addition, exonic mutations have been found to be highly infrequent in p15 INK4b in any tumor type.…”

Section: Mouse P15 Ink4b and P16 Ink4a Cpg Islands Are Hypermethylatementioning

confidence: 99%

Inactivation of the cyclin-dependent kinase inhibitor p15INK4b by deletion and de novo methylation with independence of p16INK4a alterations in murine primary T-cell lymphomas

et al. 1997

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A wide panel of murine induced T-cell lymphomas have been analysed for p16 INK4a or p15 INK4b alterations. Only one g-radiation-induced lymphoma showed p16 INK4a homozygous deletion and no other intragenic mutations were found in these INK4 genes. However, de novo methylation of the 5' CpG islands of the murine p15 INK4b and p16 INK4a genes was found to be highly frequent. While p16 INK4a hypermethylation was found in 36% of the neutron-radiation-induced lymphomas and 15% of the gradiation-induced lymphomas, de novo methylation of p15 INK4b occurs in 88% and 42% of these tumors respectively, correlating with de®cient expression of the corresponding mRNA and allelic losses in the p15 INK4b and p16 INK4a chromosome location. These data represent, to our knowledge, the ®rst report on the signi®cant involvement of hypermethylation of these INK4 genes in murine primary tumors. Moreover, they show the importance of allelic losses and CpG island methylation of p15 INK4b gene inactivation and support a tumor suppressor role for p15 INK4b in T-cell lymphomas independent of p16 INK4a .

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Section: Mouse P15 Ink4b and P16 Ink4a Cpg Islands Are Hypermethylatementioning

confidence: 99%

Inactivation of the cyclin-dependent kinase inhibitor p15INK4b by deletion and de novo methylation with independence of p16INK4a alterations in murine primary T-cell lymphomas

et al. 1997

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“…In some cases of acute lymphocytic leukaemia, however, p16INK4a sequences were spared while p15INK4b and p19ARF sequences were speci®cally deleted (Heyman et al, 1996). Likewise, two human melanoma cell lines, A375 and SK-Mel93 sustained localized homozygous deletions of exon 1b while exons 1a, 2 and 3 remained intact allowing expression of p16INK4a transcripts (Stone et al, 1995b).…”

Section: Introductionmentioning

confidence: 99%

Expression of p16INK4a/p16α and p19ARF/p16β is frequently altered in non-small cell lung cancer and correlates with p53 overexpression

et al. 1998

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The CDKN2 locus expresses two di erent mRNA transcripts, designated a and b. The protein product of the a transcript is the cell cycle inhibitor and tumour suppressor p16INK4a. The b transcript is translated in an alternate reading frame (ARF) and in humans encodes a 15 kDa protein (p19ARF). Immunohistochemical and Western analysis of p16INK4a has shown that the protein is downregulated in a signi®cant number of tumours, but less is known on the expression of the p19ARF. We have examined the expression of p16INK4a and p19ARF in resectable non-small cell lung cancer (NSCLC) by immunostaining (n=49) and multiplex RT ± PCR (n=28). In order to investigate the mechanism responsible for p16INK4a downregulation, exon 1a methylation was analysed in a PCR-based assay. Of 49 tumours examined by immunostaining, 24 and 20 tumours expressed p16INK4a and p19ARF at nil to low levels, respectively. p19ARF was localized primarily to the nuclei of tumour cells, but was also seen to varying degrees in nuclei of lymphocytes, chondrocytes, ®broblasts, and epithelial cells. No tumour with normal p16INK4a had decreased p19ARF expression. Among 16 tumours with nil to low p16INK4a expression, 11 tumours exhibited full methylation of at least one site within exon 1a and these tumours showed normal p19ARF expression. In contrast, no methylation of exon 1a was observed in ®ve tumours which also lacked p19ARF. In normal lung, p16INK4a and p19ARF were not expressed at detectable levels, the multiplex RT ± PCR results were balanced, and sites within exon 1a were strongly methylated. In tumours, imbalanced multiplex RT ± PCR data (p16INK4a5p19ARF) predicted methylation of exon 1a (P=0.0006) as well as downregulation of p16INK4a. p19ARF downregulation was inversely correlated with p53 overexpression (P=0.025), whilst negative immunostaining for p16INK4a was inversely correlated with pRb downregulation (P=0.003) and directly correlated with p53 overexpression as assessed by immunostaining (P=0.015). Our results show that: (1) p16INK4a and p19ARF expression are altered in almost half of resectable NSCLC; (2) methylation within exon 1a is a frequent, but not the only mechanism of p16INK4a downregulation; and that (3) the inverse association of p19ARF and p53 alteration is consistent with a linked pathway.

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“…Heyman et al, 7 however, showed, in a small group (n ¼ 24 for homozygous deletions, n ¼ 12 for hemizygous deletions), a difference in prognostic value between homoand hemizygous deletions using Southern blot combined with microsatellite analysis. 7 Future investigations on larger patient groups will have to provide more insight into the prognostic value of each type of deletion.…”

Section: To the Editormentioning

confidence: 99%

CDKN2 deletions have no prognostic value in childhood precursor-B acute lymphoblastic leukaemia

et al. 2005

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Prognostic importance of p15INK4B and p16INK4 gene inactivation in childhood acute lymphocytic leukemia.

Abstract: The data suggest that analysis of p15INK4B/p16INK4 genes may contribute prognostic information in pediatric ALL.

Cited by 72 publications

References 0 publications

Inactivation of the cyclin-dependent kinase inhibitor p15INK4b by deletion and de novo methylation with independence of p16INK4a alterations in murine primary T-cell lymphomas

Inactivation of the cyclin-dependent kinase inhibitor p15INK4b by deletion and de novo methylation with independence of p16INK4a alterations in murine primary T-cell lymphomas

Expression of p16INK4a/p16α and p19ARF/p16β is frequently altered in non-small cell lung cancer and correlates with p53 overexpression

CDKN2 deletions have no prognostic value in childhood precursor-B acute lymphoblastic leukaemia

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