Deletions of p15 and/or p16 genes as a poor-prognosis factor in adult T-cell leukemia.

Yamada, Yasuaki; Hatta, Yoshihiro; Murata, Ken T.; Sugawara, Kazuyuki; Ikeda, Shu‐ichi; Mine, Mariko; Maeda, Takahiro; Hirakata, Yoichi; Kamihira, Shimeru; Tsukasaki, Kunihiro; Ogawa, Seishi; Hirai, Hiroshi; Koeffler, HP; Tomonaga, Masao

doi:10.1200/jco.1997.15.5.1778

Cited by 112 publications

(61 citation statements)

References 28 publications

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“…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. 39,90 A separate set of data correlates the events of disease progression (for instance patients at diagnosis vs patients at relapse) and transformation (eg from MDS to overt leukemia) ( Table 5). Two types of analyses were reported: comparison of unpaired cohorts where, for example, patients of cohort 1 examined at diagnosis were different from the patients of cohort 2 investigated at relapse.…”

Section: Prognostic Relevance Of P15 and P16 Alterationsmentioning

confidence: 99%

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%

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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“…They also have been reported in primary cancers of the lung (Nobori et al, 1994;Okami et al, 1997;Schmid et al, 1998), bladder (Balazs et al, 1997;Orlow et al, 1995;Stadler and Olopade, 1996), head and neck (Gonzalez et al, 1997;Matsuura et al, 1998;Waber et al, 1997), as well as in acute T cell leukemias (Hatta et al, 1995;Hori et al, 1998;Yamada et al, 1997), and mesotheliomas (Kratzke et al, 1995). Since inherited mutations of p16 INK4A exon 2 may interfere with its expression and/or function, without causing an amino acid change in p14 ARF , it is clear that p16 INK4A inactivation alone is an important step in the evolution of malignant disease.…”

Section: Introductionmentioning

confidence: 99%

A methylthioadenosine phosphorylase (MTAP) fusion transcript identifies a new gene on chromosome 9p21 that is frequently deleted in cancer

et al. 2000

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“…25 The deletion of p16 gene predicts the shortened survival in ATL and plays a key role in the progression of the disease from chronic to acute form. 26,27 Although no such relationship existed at diagnosis, p16 deletion was associated with the shorter survival in patients with relapsed T-ALL. 28 Since chromosome 9p deletions in ATL and T-ALL predict prognosis, a precise and accurate diagnostic method for detection of such gene deletions is needed.…”

Section: Introductionmentioning

confidence: 99%

Detection of methylthioadenosine phosphorylase (MTAP) and p16 gene deletion in T cell acute lymphoblastic leukemia by real-time quantitative PCR assay

et al. 2000

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Deletions of p15 and/or p16 genes as a poor-prognosis factor in adult T-cell leukemia.

Abstract: The results suggest the following: (1) that the deletions of p15 and/or p16 genes play a key role in the progression of ATL; and (2) that these deletions are reliable prognostic factors that predict shortened survival times.

Cited by 112 publications

References 28 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

A methylthioadenosine phosphorylase (MTAP) fusion transcript identifies a new gene on chromosome 9p21 that is frequently deleted in cancer

Detection of methylthioadenosine phosphorylase (MTAP) and p16 gene deletion in T cell acute lymphoblastic leukemia by real-time quantitative PCR assay

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