The <i>CDKN2</i> gene alterations in various types of adult T‐cell leukaemia

Uchida, Toshiki; Kinoshita, Tomohiro; Watanabe, Takashi; Nagai, Hirokazu; Murate, Takashi; Saito, Hidehiko; Hotta, Tomomitsu

doi:10.1046/j.1365-2141.1996.d01-1841.x

Cited by 38 publications

(24 citation statements)

References 25 publications

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“…Since p15 Ink4b induces growth arrest associated with differentiation or apoptosis, it is not usually expressed in normal or transformed proliferating hematopoietic cells (Herman et al, 1997;Iravani et al, 1997;Malumbres et al, 1997;Uchida et al, 1997;Malumbres et al, 1999). In the present study, we found that transformed murine monocytic cells with exogenously expressed c-Myc were an exception.…”

Section: Discussionmentioning

confidence: 37%

Consistent inactivation of p19Arf but not p15Ink4b in murine myeloid cells transformed in vivo by deregulated c-Myc

Haviernik

Schmidt

et al. 2003

Oncogene

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Cyclin-dependent kinase inhibitors p16 INK4a and p15 INK4b , encoded by the CDKN2A and B loci, play an important role in negative regulation of the cell cycle. Furthermore, p19 ARF also encoded by the CDKN2A locus, has been shown to regulate positively the p53 pathway leading to growth arrest and apoptosis. All three genes have been inactivated in human tumors. In myeloid cells, p15 INK4b mRNA is upregulated during cytokine-induced differentiation and/or growth arrest, and hypermethylation of the p15 INK4b gene promoter region is a common event in acute myeloid leukemia. In the present study, we examined murine monocyte/macrophage tumors with deregulated cmyc for evidence of Ink4 gene inactivation. p15 Ink4b mRNA and protein were detected in the majority of leukemias, and p16 Ink4a mRNA and protein were highly expressed in two of them. pRb was in a hypophosphorylated state in most of the neoplasms indicating that the Cdk inhibitors that were expressed in the cells were functional. The observed expression of p15 Ink4b is inconsistent with their proliferation state, although it might be expected to be expressed owing to the maturity of the cells. These data suggest, therefore, that deregulated cMyc bypasses the pRb restriction point and cell cycle arrest in these tumors. An examination of p19 Arf exons revealed deletions of the gene in up to 94% of the tumors. Since this gene shares exon 2 with p16 Ink4a , it is often difficult to determine which gene is the relevant tumor suppressor. However, the loss of only the p19 Arf -specific exon 1b was observed in a tumor that had normal p16 Ink4a protein expression. In addition, the p19 Arf -specific exon was deleted in another tumor that expressed a functional chimeric protein, p15Ex1-p16Ex2-3; it was demonstrated here that this fusion protein is capable of inducing G1 arrest. These data overall supports the hypothesis that the critical inactivation event in these hematopoietic neoplasms is elimination of p19 Arf , and not Ink4 function.

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Section: Discussionmentioning

confidence: 37%

Consistent inactivation of p19Arf but not p15Ink4b in murine myeloid cells transformed in vivo by deregulated c-Myc

Haviernik

Schmidt

et al. 2003

Oncogene

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“…This region is deleted in a wide variety of other human tumors including squamous cell carcinoma of the bladder (GonzalezZulueta et al, 1995;Cairns et al, 1995a), non small cell lung carcinoma (de Vos et al, 1995), B cell lymphoma (Uchida et al, 1995) pancreatic cancer (Caldas et al, 1994), glioma , esophegeal carcinoma (Liu et al, 1995) and melanoma (Kamb et al, 1994b). Frequent loss at 9p21 ± 22 occurs as an early event in head and neck cancer progression and was found in both invasive and preinvasive lesions (Van de Riet et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Genetic alterations of chromosome band 9p21 – 22 in head and neck cancer are not restricted to p16INK4a

et al. 1997

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Although genetic alterations of chromosome band 9p21 ± 22 occur frequently in head and neck squamous cell carcinoma (HNSCC) cell lines, alterations of the cyclindependent kinase inhibitor p16 INK4a located in this region are less common in corresponding primary tumors. To further investigate genetic alterations at 9p21 ± 22 and p16 INK4a in primary HNSCC, a paired set of 21 tumors and blood specimens that were shown previously to exhibit allelic loss at 3p and elsewhere, were tested for LOH at 9p21 ± 22 using eight di erent highly polymorphic marker. Sixteen of the samples (81%) exhibited LOH for at least one marker. Frequent LOH was found surrounding p16 INK4a and at three additional noncontiguous regions of 9p21 ± 22. No homozygous deletions were identi®ed. SSCP screening and direct sequence analysis led to the identi®cation of mutations the p16 INK4a gene in two tumors. p16 INK4a was not hypermethylated in any of the samples studied. Furthermore, there was no correlation between LOH at 9p21 ± 22 and the RB1 tumor suppressor gene. These ®ndings indicate that in the set of tumors that we tested, LOH at 9p21 ± 22 is common in primary HNSCC but that genetic alterations of p16 INK4a located in this region are unusual. Additional tumor suppressor genes at 9p21 ± 22 may therefore be involved in the pathogenesis of this tumor.

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“…92,[139][140][141][142][143][144][145] Several investigators including ourselves have reported alterations of the p16 occurring in 17-68% of the acute and 5-26% of the chronic ATLL samples and the p15 gene was structurally abnormal in 21-30% of the acute and 0-13% of the chronic ATLL specimens. 90,[146][147][148][149][150] In total, genomic alterations of the p16 gene occurred in 55 of 136 acute/ lymphomatous (40%) cases and nine of 79 (11%) chronic/smoldering ATLL samples. For the p15 gene, 30 of 111 (27%) acute/lymphomatous cases and three of 60 (5%) chronic/smoldering ATLL samples had alterations.…”

Section: Role Of Ink4 Family In Atllmentioning

confidence: 99%

Role of tumor suppressor genes in the development of adult T cell leukemia/lymphoma (ATLL)

Hatta

Koeffler

2002

Leukemia

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The CDKN2 gene alterations in various types of adult T‐cell leukaemia

Cited by 38 publications

References 25 publications

Consistent inactivation of p19Arf but not p15Ink4b in murine myeloid cells transformed in vivo by deregulated c-Myc

Consistent inactivation of p19Arf but not p15Ink4b in murine myeloid cells transformed in vivo by deregulated c-Myc

Genetic alterations of chromosome band 9p21 – 22 in head and neck cancer are not restricted to p16INK4a

Role of tumor suppressor genes in the development of adult T cell leukemia/lymphoma (ATLL)

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