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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human T-cell leukemia virus type 1 is etiologically linked to the development of adult T-cell leukemia and various human neuropathies. The Tax protein of human T-cell leukemia virus type I has been implicated in cellular transformation. Like other oncoproteins, such as Myc, Jun, and Fos, Tax is a transcriptional activator. How it mechanistically dysregulates the cell cycle is unclear. Previously, it was suggested that Tax affects cell-phase transition by forming a direct protein-protein complex with p16(INK4a), thereby inactivating an inhibitor of G1-to-S-phase progression. Here we show that, in T cells deleted for p16(INK4a), Tax can compel an egress of cells from G0/G1 into S despite the absence of serum. We also show that in undifferentiated myocytes, expression of Tax represses cellular differentiation. In both settings, Tax expression was found to increase cyclin D-cdk activity and to enhance pRb phosphorylation. In T cells, a Tax-associated increase in steady-state E2F2 protein was also documented. In searching for a molecular explanation for these observations, we found that Tax forms a protein-protein complex with cyclin D3, whereas a point-mutated and transcriptionally inert Tax mutant failed to form such a complex. Interestingly, expression of wild-type Tax protein in cells was also correlated with the induction of a novel hyperphosphorylated cyclin D3 protein. Taken together, these findings suggest that Tax might directly influence cyclin D-cdk activity and function, perhaps by a route independent of cdk inhibitors such as p16(INK4a).
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PMID:Human T-cell leukemia virus type 1 Tax and cell cycle progression: role of cyclin D-cdk and p110Rb. 958 3

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 (bi- or monoallelic) or 5' 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 p15del and p16del were seen in acute lymphoblastic leukemia (ALL) (>30%) with striking rates in T-ALL (>50%), but also high rates in B cell precursor (BCP)-ALL (>20%); 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% p15met in AML, MDS and multiple myeloma. Also p15met rates in BCP- and 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. p15del/p16del and p15met/p16met 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 G1 (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 p16 inactivation with p53 was detected. Paired analysis of cell lines and corresponding primary cell material showed that in all instances tested both populations carried the same gene configuration of p15 and p16. Thus, p15del or p16del did not occur during establishment of the cell lines or during prolonged culture. It is likely that p15 or p16 deletions already acquired in vivo provide a dramatic growth advantage for the immortalization process in vitro, thus increasing the success rate for cell line establishment which is commonly extremely difficult. In conclusion, the present review suggests an involvement of the p15 and p16 tumor suppressor genes in leukemo- and lymphomagenesis. Future studies will determine their exact role in the development and progression of hematopoietic neoplasms. These genes may represent interesting targets for new therapeutic strategies.
Leukemia 1998 Jun
PMID:Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia-lymphoma cells. 963 10

P15 (MTS2) gene is a candidate tumor suppressor gene localized adjacent to the p16 gene at 9p21. Deletions at the 9p21 region frequently affect both p16 and p15 genes, however, mutations in the coding sequence of the p15 gene have not been found in the majority of tumors analyzed, including non-Hodgkin's lymphomas. Abnormal methylation of the promoter region of p15 has been recently described as an alternative mechanism of inactivation of this gene. We analyzed 72 non-Hodgkin's lymphomas (NHL) for methylation at p15 exon 1 by PCR and Southern blot techniques using methylation-sensitive restriction enzymes. Abnormal methylation was found in eight cases (11%), most of them (three MALT, one anaplastic T cell lymphoma, one Burkitt and one follicular lymphoma) showing hypermethylation in the p16 gene also. In contrast, two pleomorphic T cell NHL showed a selective methylation at p15 gene, while the p16 gene remained unmethylated. The results show that methylation at the p15 gene is frequently associated with p16 methylation in NHL, and suggest that selective methylation of p15, although uncommon, could be a specific alteration implicated in T cell NHL.
Leukemia 1998 Jun
PMID:Hypermethylation of p15/ink4b/MTS2 gene is differentially implicated among non-Hodgkin's lymphomas. 963 23

Mantle cell lymphomas (MCL) are morphologically and immunophenotypically distinctive lymphoid neoplasms characterised by overexpression of cyclin D1. Recent studies have suggested that co-operating aberrations of cell cycle associated genes may provide a growth advantage to a tumour. To address this issue further, we investigated five typical and three aggressive (blastoid) MCL for alterations in the cell cycle regulating genes p15, p16, CDK4, Rb and p53. In 3/3 aggressive cases with cyclin D1 overexpression we found aberration of at least one additional gene. One case showed diminished expression of the retinoblastoma protein (pRb); one case harboured deletion of both p15 and p16; and one case exhibited both deletion of p16 and point mutation of p53. However, we also identified two typical cases which in addition to cyclin D1 overexpression exhibited diminished pRb expression and p15 and p16 hypermethylation, respectively. Our findings confirm and extend other recent investigations and indicate that co-operating genetic alterations of cell cycle-associated genes may contribute to the pathogenesis of MCL.
Leukemia 1998 Aug
PMID:Concurrent disruption of cell cycle associated genes in mantle cell lymphoma: a genotypic and phenotypic study of cyclin D1, p16, p15, p53 and pRb. 969 82

The human T-cell leukemia virus type I (HTLV-I) is a causative agent of adult T-cell leukemia. Although the exact mechanism by which HTLV-I contributes to leukemogenesis is still unclear, the Tax protein is thought to play a major role in this process. This 40-kDa polypeptide is able to interact with the tumor suppressor p16(INK4A). Consequently, Tax can activate the signaling pathway that lead to the release of E2F that in turn induces expression of factors required for cell cycle progression. In this paper, we demonstrate that Tax can also activate E2F-mediated transcription independently of p16(INK4A). Indeed, when Tax is coexpressed with the E2F-1 transcription factor in CEM T-cells, which lack expression of p16(INK4A), it strongly potentiates the E2F-dependent activation of a reporter construct driven by a promoter containing E2F binding sites. This stimulation is abrogated by mutations affecting the E2F-binding sites. In addition, Tax also stimulates the transcription of the E2F-1 gene itself. Using Tax mutants that fail to activate either ATF- or NF-kappaB-dependent promoters and different 5' truncation mutants of the E2F-1 promoter, we show that the Tax-dependent transcriptional control of the E2F1 gene involves, at least in part, the ATF binding site located in the E2F-1 promoter.
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PMID:Activation of E2F-mediated transcription by human T-cell leukemia virus type I Tax protein in a p16(INK4A)-negative T-cell line. 972

The Ink4a/Arf locus encodes p16(Ink4a) and p19(Arf) and is among the most frequently mutated tumor suppressor loci in human cancer. In mice, many of these effects appear to be mediated by interactions between p19(Arf) and the p53 tumor-suppressor protein. Because Tp53 mutations are a common feature of the multistep pre-B cell transformation process mediated by Abelson murine leukemia virus (Ab-MLV), we examined the possibility that proteins encoded by the Ink4a/Arf locus also play a role in Abelson virus transformation. Analyses of primary transformants revealed that both p16(Ink4a) and p19(Arf) are expressed in many of the cells as they emerge from the apoptotic crisis that characterizes the transformation process. Analyses of primary transformants from Ink4a/Arf null mice revealed that these cells bypassed crisis. Because expression of p19(Arf) but not p16 (Ink4a) induced apoptosis in Ab-MLV-transformed pre-B cells, p19(Arf) appears to be responsible for these events. Consistent with the link between p19(Arf) and p53, Ink4a/Arf expression correlates with or precedes the emergence of cells expressing mutant p53. These data demonstrate that p19(Arf) is an important part of the cellular defense mounted against transforming signals from the Abl oncoprotein and provide direct evidence that the p19(Arf)-p53 regulatory loop plays an important role in lymphoma induction.
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PMID:p19(Arf) induces p53-dependent apoptosis during abelson virus-mediated pre-B cell transformation. 978 64

In acute leukemia (AL) with a late-appearing Philadelphia (la-Ph) translocation, it is unclear whether these translocations arise from the same molecular event as classical Ph translocations. In order to elucidate the molecular events of la-Ph and subsequent translocations of la-Ph leukemia, we performed molecular analysis on the complex rearrangements, in a cell line, MY, which was established from bone marrow mononuclear cells of a patient with a la-Ph acute biphenotypic leukemia. This la-Ph, expressing an acute lymphoblastic leukemia (ALL)-type BCR/ABL transcript, produces a novel P180BCR/ABL fusion protein reflecting deletion of 174 bases (58 amino acids) encoded by the a2 exon of the ABL gene. An immune complex kinase assay showed that this protein had autophosphorylation activity. Fluorescence in situ hybridization (FISH) in conjunction with G-banding analysis revealed that the initial der(9)t(9;22)(q34;q11) progressed to a der(9)(9pter-->9q34::22q11-->22q13::5q11.2 -->5q15:: 10q23-->10qter) by, first, a three-way translocation among the der(9)t(9;22)(q34;q11), chromosome 5, and the normal chromosome 22, and then a subsequent translocation with chromosome 10. Moreover, both the end-stage leukemic cells of the patient and the MY cell line had another translocation, t(X;12)(p11.2;p13). The 12p breakpoint was located near the ETV6 gene by analysis of pulsed-field gel electrophoresis, but transcription of ETV6 was unaffected. Tumorigenicity analysis indicated that an additional translocation, t(2;3)(p16;q29), may have caused a more malignant clone, because only MY cells with the t(2;3)(p16;q29) were capable of growing subcutaneously in nude mice within 40 days. The molecular events of leukemogenesis and leukemic progression in the present la-Ph AL occurred by accumulation of unique translocations. This cell line, MY, expressing a novel variant P180BCR/ABL protein with a deletion of the a2 exon of the ABL gene, may be useful for elucidating the pathophysiology of this fusion protein and for studying ETV6-related leukemogenesis and t(2;3), as well as the molecular mechanisms of the complex translocations.
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PMID:Establishment of a cell line with variant BCR/ABL breakpoint expressing P180BCR/ABL from late-appearing Philadelphia-positive acute biphenotypic leukemia. 979 May 3

Homozygous deletion of the p16 tumour suppressor gene (at frequencies ranging from 14% to 29%) have been implicated in the pathogenesis of acute lymphoblastic leukaemia (ALL) by several studies. We investigated the prevalence of this deletion in a group of 46 Arab patients with common ALL. Deletion of p16 was assessed in a multiplex PCR which amplified a 405 bp fragment from exon 2 of the p16 gene, and a 242 bp fragment of the ApoE lipoprotein gene which served as an internal control. Homozygous deletion of p16 in tumour cells could be readily detected in samples containing >75% blasts. Surprisingly, none of the cases in our study showed homozygous deletion of the p16 gene. We also investigated the possibility of other genetic alterations in the p16 gene or mutation in the p21 and CDK4 (not previously reported in ALL) genes which are part of the same signal transduction pathway. A heterozygous G --> A transition at nucleotide position 273 of the p16 gene was present in one patient, but did not result in an amino acid change. A C --> A transversion at codon 88 of the p21 gene, which results in replacement of a phenylalanine with a leucine at position 63, was detected in one patient. In another patient a G --> C transversion in exon 2 at codon 82 (5'-untranslated region of the CDK4 gene) was detected. Results of this study showed mutation of p16, p21 or CDK4 to be rare events in Arab ALL patients.
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PMID:Mutation of p16, p21 or cyclin dependent kinase 4 is rare in acute lymphoblastic leukaemia. 982 21

Tax protein of human T-cell leukemia virus type 1 (HTLV-1) is a potent trans-activator of specific sets of target genes, and on the other hand, it is a trans-repressor of other sets of genes. It is also an inhibitor of the tumor suppressor protein p16(INK4a) and thus has been thought to contribute to induction of adult T-cell leukemia (ATL). We examined the mutagenic effects of Tax on a cellular gene, hypoxanthine guanine phosphoribosyltransferase (hprt), and LacI gene in lambda shuttle vector exogenously integrated in Big Blue Rat-2 (BBRat-2) cells. Expression of Tax in BBRat-2 cells enhanced the frequency of HPRT(-) phenotype severalfold. Tax-expressing cell clones, BBTax-1 and -2 established from BBRat-2 cells, gave rise to an average mutation frequency of 5.9 x 10(-5) in LacI gene, but Tax-negative cell clones, BBRat-C1 and -C2, showed 2. 1 x 10(-5). The 2.8-fold increase in mutation frequency in the presence of Tax indicates that Tax expression enhanced mutation frequency in chromosomal DNA. However, neither the mutation spectrum of base transitions, transversions, and deletions/insertions nor the loci of the mutations were significantly affected by Tax expression. These findings indicate that Tax has the capability to induce random mutations and suggest that Tax would be able to modulate cellular phenotypes through mutation of the cellular genome.
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PMID:Trans-activator Tax of human T-cell leukemia virus type 1 enhances mutation frequency of the cellular genome. 991 74

We investigated the alterations of the p53, p21, p16, p15 and RAS genes in childhood T-cell acute lymphoblastic leukemia (T-ALL) and T-ALL cell lines by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and direct sequencing. Mutations of the p53 gene were found in three of 57 (5%) patients at diagnosis, one of 14 (7%) patients at relapse and in 12 of 18 (67%) cell lines. In these 12 cell lines, four had more than two mutations of the p53 gene. The p53 mutations were found in four of five cell lines whose original fresh leukemic cells were simultaneously examined original fresh leukemic cells. However, only one of the four fresh leukemic cells had the same mutation. All patients with p53 mutations in the course of disease died. Mutations of the p21 gene were not identified in 71 fresh samples and in 18 cell lines. N-RAS mutations were found in two of 57 (4%) fresh T-ALL patients at diagnosis, and four of 18 cell lines (22%), whereas no mutations were detected in any samples at relapse. Alterations of the p16 gene were found in 18 of 47 (38%) patients at diagnosis and in seven of 14 (50%) at relapse. These differences were not statistically significant. There were no differences in the frequency of alteration of the p16 and p15 genes between event-free patients and the remaining patients. Furthermore, we found the methylation of p16 gene in three of seven patients lacking homozygous deletions, suggesting higher frequency of p16 inactivation than previous reports in T-ALL. Interestingly, we found that one allele is inactivated by methylation and another allele had nonsense mutation in one cell line (KOPT-KI), resulting in loss of protein expression of p16. This type of p16 inactivation has not been so far reported in leukemia. We conclude that, (1) p53 mutations are infrequent at diagnosis but tend to be associated with poor clinical outcome; (2) RAS and p21 mutations may not be involved in the pathogenesis of T-ALL; (3) not only frequent alterations of p16 and p15 genes but also methylation of p16 gene are involved in initiating the leukemogenesis of T-ALLs, and (4) these 5 genes are independently involved in T-ALL.
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PMID:Alterations of the p53, p21, p16, p15 and RAS genes in childhood T-cell acute lymphoblastic leukemia. 1007 Nov 27


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