Abstract:
: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.
journal_name
Leukemiajournal_title
Leukemiaauthors
Drexler HGdoi
10.1038/sj.leu.2401043subject
Has Abstractpub_date
1998-06-01 00:00:00pages
845-59issue
6eissn
0887-6924issn
1476-5551journal_volume
12pub_type
杂志文章,评审相关文献
LEUKEMIA文献大全abstract::An antisense oligodeoxynucleotide (ODN) complementary to the first six codons of the Bcl-2 mRNA, G3139 (oblimersen sodium; Genasense), has been shown to downregulate Bcl-2 and produce responses in a variety of malignancies including drug-resistant lymphoma. Incubation of ex vivo purified plasma cells from patients wit...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2402768
更新日期:2003-01-01 00:00:00
abstract::Adults with acute lymphoblastic leukemia (ALL) do worse than children. From 7/2008 to 12/2014, Nordic and Baltic centers treated 1509 consecutive patients aged 1-45 years with Philadelphia chromosome-negative ALL according to the NOPHO ALL2008 without cranial irradiation. Overall, 1022 patients were of age 1-9 years (...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/leu.2017.265
更新日期:2018-03-01 00:00:00
abstract::These ECOG trials have demonstrated that progressive increments in the intensity of post-remission therapy result in improving long-term, disease-free survival in adults with AML. The median duration of disease-free survival and long-term outcome from different post-remission therapies are summarized in Table 4. [tabl...
journal_title:Leukemia
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:
更新日期:1992-01-01 00:00:00
abstract::Natural killer (NK) cells are the first lymphocytes to recover after allogeneic stem cell transplantation (SCT) and can exert powerful graft-versus-leukemia (GVL) effects determining transplant outcome. Conditions governing NK cell alloreactivity and the role of NK recovery in sibling SCT are not well defined. NK cell...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2404892
更新日期:2007-10-01 00:00:00
abstract::The hybridization to a complementary RNA (cRNA) probe both in situ and in solution was used to assay tiny amounts of mRNA of the lactoferrin (LF) and myeloperoxidase (MPO) genes in normal bone marrow cells and in acute and chronic lymphoid leukemias. Evidence is reported that this technique is much more sensitive than...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1990-10-01 00:00:00
abstract::Chronic lymphocytic leukemia (CLL) remains incurable with chemoimmunotherapy, and allogeneic hematopoietic stem cell transplantation (HSCT) offers the potential for cure. We assessed the outcomes of 108 CLL patients undergoing first allogeneic HSCTs, 76 with reduced-intensity (RIC) and 32 with myeloablative conditioni...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/leu.2012.228
更新日期:2013-02-01 00:00:00
abstract::Many genes are involved in cell cycle control, DNA repair and induction of cell death. Alterations in these genes have been responsible for the development of cancer as well as for resistance to cancer therapy. Recently, an emerging family of bcl2-like genes has been identified that plays a role in the regulation of c...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1995-11-01 00:00:00
abstract::Trisomy 12 is the most common chromosomal aberration in chronic B lymphocytic leukemia (B-CLL). In this study we have investigated trisomy 12 and posed two major questions: (a) What is the origin of the third copy of chromosome 12? and (b) What is the proportion of trisomy 12 cells in malignant clones with this aberra...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1989-12-01 00:00:00
abstract::Population-based studies of classical Hodgkin lymphoma (cHL) in contemporary clinical practice are scarce. The aim of this nationwide population-based study is to assess trends in primary therapy and relative survival (RS) during 1989-2017. We included 9,985 patients with cHL. Radiotherapy alone was virtually not appl...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/s41375-020-0875-0
更新日期:2020-05-28 00:00:00
abstract::The expression of the myeloperoxidase (MPO) gene was studied, by means of Northern blot analysis in 14 cases of acute myeloid leukemia (AML), 11 cases of chronic myeloid leukemia (CML), and 6 cases of CML blast crisis, and in HL60 cells before and after induction of terminal differentiation with retinoic acid (RA), ph...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1989-06-01 00:00:00
abstract::It has been suggested that abnormalities of chromosome 3 at bands q21 and q26 are associated with the presence of increased numbers of abnormal megakaryocytes in patients with hematologic malignancies. The pretreatment bone marrows of 287 patients with leukemia (acute myeloid leukemia (AML), 225 patients; acute lympho...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1990-05-01 00:00:00
abstract::Molecular analysis of T cell receptor (TCR) genes is frequently used to prove or exclude clonality and thereby support the diagnosis of suspect T cell proliferations. PCR techniques are more and more being used for molecular clonality studies. The main disadvantage of the PCR-based detection of clonal TCR gene rearran...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2400887
更新日期:1997-12-01 00:00:00
abstract::The value of the hypervariable X-linked probe M27 beta for use in the analysis of X-chromosome inactivation patterns in normal blood and bone marrow cells and in the assessment of clonality in acute myeloid leukemia (AML) blast cells has been determined. By electrophoresing samples for 30 h, heterozygosity of the M27 ...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1992-07-01 00:00:00
abstract::Some anaplastic large cell lymphomas (ALCLs) carry a specific chromosomal translocation, t(2;5)(p23;q35). Recently, we found a novel hyperphosphorylated 80-kDa protein tyrosine kinase, p80, in ALCLs with t(2;5). Subsequent cDNA cloning revealed p80 to be a fusion protein of two genes, the novel tyrosine kinase gene an...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1997-04-01 00:00:00
abstract::A prospective multicenter study was performed to investigate the clinical and molecular results of intensified double induction therapy including high-dose cytarabine (ara-C) in combination with ATRA in newly diagnosed acute promyelocytic leukemia (APL), followed by consolidation and 3 years maintenance therapy. Fifty...
journal_title:Leukemia
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1038/sj.leu.2401843
更新日期:2000-08-01 00:00:00
abstract::The AML1 is the most commonly involved transcription factor gene in human leukemias and forms chimeric transcription factor genes, namely, AML1/MTG8 by the t(8;21), AML1/EVI-1 by the t(3;21), and TEL/AML1 by the t(12;21). The AML1a and AML1b, two isoforms of the AML1 protein, are translated from the AML1 gene by the a...
journal_title:Leukemia
pub_type: 杂志文章,评审
doi:
更新日期:1997-04-01 00:00:00
abstract::Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with dif...
journal_title:Leukemia
pub_type: 杂志文章,评审
doi:10.1038/leu.2012.336
更新日期:2013-04-01 00:00:00
abstract::The non-obese diabetic-severe combined immunodeficiency (NOD-SCID) mouse is a convenient host for human hematopoietic tissues and cells. Human fetal bone fragments engrafted subcutaneously in NOD-SCID mice sustain human hematopoiesis for several months. MS5 murine bone marrow stromal cells were transfected by electrop...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2401081
更新日期:1998-07-01 00:00:00
abstract::To guide development of new clinical strategies, a review of recent investigations in the pathobiology of MDS was performed. Articles were identified through a Medline search. Studies, including reviews, are cited in the references. A multistep pathogenesis is proposed. (1) Targeted injury or mutation within hemopoiet...
journal_title:Leukemia
pub_type: 杂志文章,评审
doi:10.1038/sj.leu.2401618
更新日期:2000-01-01 00:00:00
abstract::A patient with the M2 subtype of AML who had a 45,X,-X,t(8;21) karyotype at diagnosis was found to have the Ph chromosome in one out of 37 evaluated cells 18 months after the initial diagnosis. Interphase FISH studies utilizing a BCR-ABL dual-color probe did not detect a fusion product 4 months prior to the appearance...
journal_title:Leukemia
pub_type: 杂志文章,评审
doi:10.1038/sj.leu.2400974
更新日期:1998-04-01 00:00:00
abstract::Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells. To investigate whether chromosomal instability and/or DNA repair defects are involved in the development of MDS, we measured the micronucleus (MN) frequency in peripheral blood lymphocytes exposed to various doses of X-rays, using a cytok...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2402703
更新日期:2002-11-01 00:00:00
abstract::The aim of this study was to collect prospectively unselected, population-based data on young adults with acute myeloid leukaemia (AML) over a 9-year period and to evaluate the impact on survival of the introduction of allogeneic transplantation performed in first remission. The population within the Northern Region o...
journal_title:Leukemia
pub_type: 临床试验,杂志文章
doi:
更新日期:1995-07-01 00:00:00
abstract::In all, 17 consecutive patients in hematological complete remission (HCR) of acute promyelocytic leukemia (APL) received allogeneic stem cell transplantation (SCT) from an HLA-identical sibling and were monitored by reverse transcriptase polymerase chain reaction of PML/RARalpha prior and after transplant. Median age ...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2403078
更新日期:2003-10-01 00:00:00
abstract::The occurrence of leukemia in a gene therapy trial for SCID-X1 has highlighted insertional mutagenesis as an adverse effect. Although retroviral integration near the T-cell acute lymphoblastic leukemia (T-ALL) oncogene LIM-only protein 2 (LMO2) appears to be a common event, it is unclear why LMO2 was preferentially ta...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2404563
更新日期:2007-04-01 00:00:00
abstract::Outcomes after unmanipulated haploidentical stem cell transplantation (Haplo) and after unrelated cord blood transplantation (UCBT) are encouraging and have become alternative options to treat patients with high-risk acute leukemia without human leukocyte antigen (HLA) matched donor. We compared outcomes after UCBT an...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/leu.2015.98
更新日期:2015-09-01 00:00:00
abstract::A relationship was proved between constitutive activity of leukemic cell c-jun-N-terminal kinase (JNK) and treatment failure in AML. Specifically, early treatment failure was predicted by the presence of constitutive JNK activity. The mechanistic origins of this association was sought. A multidrug resistant leukemic c...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2402457
更新日期:2002-05-01 00:00:00
abstract::In order to improve leukemia-free survival (LFS) without the treatment-related morbidity of allogeneic bone marrow transplantation or multiple prolonged cycles of consolidation chemotherapy, we evaluated the long-term outcome of autologous transplantation of peripheral blood progenitor cells (PBPCs) as postremission t...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2403126
更新日期:2003-11-01 00:00:00
abstract::The introduction of BCR-ABL tyrosine kinase inhibitors has revolutionized the treatment of chronic myeloid leukemia (CML). A major clinical aim remains the identification and elimination of low-level disease persistence, termed "minimal residual disease". The phenomenon of disease persistence suggests that despite tar...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/s41375-019-0684-5
更新日期:2020-06-01 00:00:00
abstract::Recent evidence has established an important role for leukemia inhibitory factor (LIF) as hematopoietically active cytokine. The present study utilized two different murine bone marrow stromal cell lines, +/+-1.LDA11 and MBA-13, to define regulatory mechanisms of LIF messenger RNA (mRNA) induction. LIF mRNA was not de...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1993-04-01 00:00:00
abstract::Event-free survival (EFS) at 5 years in pediatric acute lymphoblastic leukemia (ALL) is >80%. Outcome in adult ALL is still unsatisfactory, which is due to less cumulative dosing of chemotherapy and less strict adherence to timing of successive cycles. In the present phase II trial, we evaluated a pediatric regimen in...
journal_title:Leukemia
pub_type: 杂志文章,多中心研究
doi:10.1038/leu.2011.141
更新日期:2011-11-01 00:00:00