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Clinical significance of p53 mutations in relapsed T-cell acute lymphoblastic leukemia 总被引:3,自引:0,他引:3
In T-cell acute lymphoblastic leukemia (T-ALL), p53 gene mutations were found in 12 of 51 patients in first relapse (24%). In a retrospective study, bone marrow samples at diagnosis were obtained from 9 of the 12 relapsed patients with p53 mutation; only one patient was found to harbor a p53 mutation at diagnosis. No further p53 mutations were identified in 18 unpaired diagnosis T-ALL samples. This is the first report of a p53 mutation in T-ALL at diagnosis. p53 mutations in relapsed T-ALL were clinically relevant. Patients with p53 mutations experience a shorter duration of survival than those patients without p53 mutations. Additionally, patients with p53 mutations were significantly less likely to have achieved a complete second remission from reinduction therapy than those patients without p53 mutations and experience a shorter duration of survival from relapse even when a second reinduction is obtained. Though primarily identified only at relapse, p53 mutations were also associated with a decreased duration of first remission and overall decrease in survival from diagnosis. Patients with p53 mutations had a 3.8-fold increase in risk of death than those patients without p53 mutations. These findings suggest that p53 mutation is associated with poor clinical outcome that is characterized by (1) a shortened duration of survival after first relapse; (2) a reduced response to reinduction therapy; (3) a shortened duration of first remission; and, hence, (4) an overall decreased duration of survival and increased risk of death. 相似文献
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Homozygous deletions of p16/MTS1 gene are frequent but mutations are infrequent in childhood T-cell acute lymphoblastic leukemia 总被引:7,自引:1,他引:6
Ohnishi H; Kawamura M; Ida K; Sheng XM; Hanada R; Nobori T; Yamamori S; Hayashi Y 《Blood》1995,86(4):1269-1275
Fifty-six primary childhood T-cell acute lymphoblastic leukemia (T-ALL) samples and 17 T-ALL cell lines were examined for mutations and homozygous deletions of the p16/MTS1 gene using polymerase chain reaction single-strand conformation polymorphism and Southern blot analysis. Homozygous deletions were found in 22 primary samples (39%) and in 10 cell lines (59%). In contrast, mutations including small deletions and/or insertions were identified in only 4 primary samples (7%) and in 2 cell lines (12%). Mutations included samples (7%) and in 2 cell lines (12%). Mutations included one nonsense mutation at codon 72, one missense mutation at codon 58, one deletion (29 bp from codon 52-61), one insertion (7 bp into codon 50), and two deletion/insertions (codon 63 and intron 1). Four of the six mutations caused subsequent stop codon and presumably produced truncated p16 protein. Our results suggest that p16 gene alterations are involved in the development of T- ALLs and that the inactivation of the p16 gene occurs mainly through homozygous deletions rather than mutations. 相似文献
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The T-cell variant accounts for about 15 to 25% of acute lymphoblastic leukemias in children and adults. In this perspective article. Drs. Chiaretti and Foà examine our present understanding of this disorder. See related article on page 224.T-cell acute lymphoblastic leukemia (T-ALL) accounts for about 15% and 25% of ALL in pediatric and adult cohorts respectively.1 Patients usually have high white blood cell counts and may present with organomegaly, particularly mediastinal enlargement and CNS involvement. The biological knowledge of TALL has until recently been rather limited. Flow cytometry allowed the stage of differentiation of the leukemic clone to be defined, while cytogenetic analyses were often uninformative. The introduction of novel technologies has allowed an increasing number of alterations to be unraveled. The most relevant results have been obtained by using FISH (Fluorescent In Situ Hybridization), molecular biology and gene expression profiling, which have enabled five subgroups to be recognized, i.e. immature/LYL1, TAL1, HOX11, HOX11L2 and HOX.2The most important biological findings of T-ALL, their role in leukemia initiation and their possible therapeutic implications will be hereby revised. 相似文献
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P53 gene mutations in acute myeloid leukemia with 17p monosomy 总被引:4,自引:2,他引:4
Fenaux P; Jonveaux P; Quiquandon I; Lai JL; Pignon JM; Loucheux-Lefebvre MH; Bauters F; Berger R; Kerckaert JP 《Blood》1991,78(7):1652-1657
We looked for mutations of exons 5 to 8 of the P53 gene in 10 patients with acute myeloid leukemia (AML) and 17p monosomy, and 36 patients with AML and no cytogenetic abnormalities of 17p. DNA was analyzed by polymerase chain reaction, single-strand conformation polymorphism analysis, and nucleotide sequencing. Four of the 10 patients with 17p monosomy showed point mutation, single-nucleotide deletion, or insertion in exons 7 or 8. By contrast, only 1 of the 36 patients with AML and no cytogenetic abnormalities of 17p showed a mutation of the P53 gene in exons 5 to 8 (P less than .01). These results suggest that alterations of the P53 gene may have a role in leukemogenesis in some cases of AML. The fact that P53 gene mutations occurred more often in patients with 17p monosomy seems to support the "recessive" model of tumor suppressive activity of the P53 gene rather than the "dominant" model, in which alteration of only one allele is sufficient for the development of malignancy. 相似文献
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Wang Q Qiu H Jiang H Wu L Dong S Pan J Wang W Ping N Xia J Sun A Wu D Xue Y Drexler HG Macleod RA Chen S 《Haematologica》2011,96(12):1808-1814
Background
Mutations in the PHF6 gene were recently described in patients with T-cell acute lymphoblastic leukemia and in those with acute myeloid leukemia. The present study was designed to determine the prevalence of PHF6 gene alterations in T-cell acute lymphoblastic leukemia.Design and Methods
We analyzed the incidence and prognostic value of PHF6 mutations in 96 Chinese patients with T-cell acute lymphoblastic leukemia. PHF6 deletions were screened by real-time quantitative polymerase chain reaction and array-based comparative genomic hybridization. Patients were also investigated for NOTCH1, FBXW7, WT1, and JAK1 mutations together with CALM-AF10, SET-NUP214, and SIL-TAL1 gene rearrangements.Results
PHF6 mutations were identified in 11/59 (18.6%) adult and 2/37 (5.4%) pediatric cases of T-cell acute lymphoblastic leukemia, these incidences being significantly lower than those recently reported. Although PHF6 is X-linked and mutations have been reported to occur almost exclusively in male patients, we found no sex difference in the incidences of PHF6 mutations in Chinese patients with T-cell acute lymphoblastic leukemia. PHF6 deletions were detected in 2/79 (2.5%) patients analyzed. NOTCH1 mutations, FBXW7 mutations, WT1 mutations, JAK1 mutations, SIL-TAL1 fusions, SET-NUP214 fusions and CALM-AF10 fusions were present in 44/96 (45.8%), 9/96 (9.4%), 4/96 (4.1%), 3/49 (6.1%), 9/48 (18.8%), 3/48 (6.3%) and 0/48 (0%) of patients, respectively. The molecular genetic markers most frequently associated with PHF6 mutations were NOTCH1 mutations (P=0.003), SET-NUP214 rearrangements (P=0.002), and JAK1 mutations (P=0.005). No differences in disease-free survival and overall survival between T-cell acute lymphoblastic leukemia patients with and without PHF6 mutations were observed in a short-term follow-up.Conclusions
Overall, these results indicate that, in T-cell acute lymphoblastic leukemia, PHF6 mutations are a recurrent genetic abnormality associated with mutations of NOTCH1, JAK1 and rearrangement of SET-NUP214. 相似文献10.
p53 mutations are associated with histologic transformation of follicular lymphoma 总被引:14,自引:2,他引:12
The majority of low-grade non-Hodgkin's lymphomas (NHL) undergo clinical progression toward intermediate- and high-grade lymphomas. This progression is often associated with histologic transformation from follicular to diffuse-type NHL. The pathogenetic mechanisms underlying this evolution are presently unknown. In this study, we have analyzed the role in NHL progression of relevant genetic lesions affecting proto-oncogenes and tumor suppressor genes. Sequential biopsies from 21 patients with clinical progression with (5 cases) or without (16 cases) evidence of histologic transformation were analyzed for karyotypic changes, c-myc rearrangements and deletions affecting 6q27 by Southern blot analysis, and p53 mutations by single-strand conformation polymorphism (SSCP) analysis coupled with direct sequencing of polymerase chain reaction-amplified products. No novel cytogenetic aberration was detected in association with progression, and all samples analyzed displayed a normal c-myc gene. Mutations of the p53 gene were detected in 4 of 5 cases displaying histologic transformation from follicular to diffuse-type NHL and in none of the 16 cases displaying clinical progression in the absence of histologic transformation. In 1 of these positive cases, the same mutation was also present in the pretransformation biopsy, correlating with the presence of diffuse-type areas within a predominant follicular pattern. In 1 of these cases, a deletion of 6q27 was also detected in the posttransformation biopsy along with a p53 mutation. These findings indicate that p53 mutations are associated with and may be responsible for histologic transformation of follicular lymphoma. 相似文献
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Outcome after relapse in childhood acute lymphoblastic leukemia 总被引:1,自引:0,他引:1
Yumura-Yagi K Hara J Horibe K Tawa A Komada Y Oda M Nishimura S Yoshida M Kudo T Ueda K;Japan Association of Childhood Leukemia Study 《International journal of hematology》2002,76(1):61-68
Among 157 children with acute lymphoblastic leukemia (ALL) who experienced relapse at 54 institutes participating in the Japan Association of Childhood Leukemia Study, we analyzed the outcomes after relapse in 103 and 30 eligible cases with bone marrow (BM) and central nervous system (CNS) relapse, respectively. Reinduction rates in BM and CNS relapse cases were 72.3% and 83.3%, respectively. High reinduction rates were observed in B-precursor (B-pre) phenotype ALL in both relapse groups and in late (more than 24 months from onset) BM-relapse patients. After BM relapse, the overall 5-year survival rate was superior in the allogeneic stem cell transplantation (SCT) group compared to the non-SCT group (41.9%+/-8.2% versus 13.6%+/-6.5%, P < .0001). In contrast, the 4-year overall survival rate was not significantly different between the SCT (allogeneic plus autologous) and non-SCT groups after CNS relapse (26.8%+/-14.2% versus 61.9%+/-12.3%, P = .252). The late BM-relapse patients showed a significantly higher survival rate than did early-relapse patients, and survival rates were similar between the allogeneic and autologous group when the patients underwent SCT during a second complete remission. Moreover, B-pre ALL patients classified in the standard-risk group according to National Cancer Institute/Rome's criteria at onset had a good prognosis after allogeneic SCT. Improving the cure rate in relapsed ALL patients requires more intensive reinduction therapy and efforts to succeed with SCT in early BM-relapse patients as well as the establishment of a treatment strategy including indications of SCT for CNS-relapse patients. 相似文献
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E Feinstein G Cimino R P Gale G Alimena R Berthier K Kishi J Goldman A Zaccaria A Berrebi E Canaani 《Proceedings of the National Academy of Sciences of the United States of America》1991,88(14):6293-6297
All patients with chronic myelogenous leukemia (CML) undergo clinical transition from chronic to acute phase. This transition is often associated with deletion of the short arm of chromosome 17 in the form of the i(17q) aberration. Since the p53 gene is a suppressor gene and is located on 17p13, we examined the possibility that it is inactivated during progression of CML. Therefore, we studied the structure and expression of p53 in the leukemic cells of a large number of CML patients in acute phase. We found that although the gene is rarely rearranged, one p53 allele is completely deleted in patients with the i(17q) aberration as well as in some patients who do not show karyotypic changes. In all of these patients the remaining allele is inactivated through loss of expression, rearrangement, or point mutation. Detailed analysis of some patients who carry both p53 alleles indicated neither loss of expression nor structural alterations. It appears that p53 loss of function is associated with progression of around 25% of CML patients. 相似文献
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Bellido M Martino R Aventín A Carnicer MJ Rubiol E López O Sierra J Nomdedéu JF 《Haematologica》2000,85(10):1083-1086
BACKGROUND AND OBJECTIVES: Lineage classification needs to be established before starting chemotherapy in acute leukemias. In some cases, mixed populations can be found and these are differentiated by antigenic expression patterns. DESIGN AND METHODS: We report the case of a patient with acute myelogenous leukemia whose relapse was classified as T-acute lymphoblastic leukemia (T-ALL). RESULTS: Flow cytometry analysis at diagnosis enabled us to identify a minor T-cell subclone which progressively increased and became dominant at relapse. There were no changes at cytogenetic and molecular levels. INTERPRETATION AND CONCLUSIONS: This case illustrates the usefulness of multiparametric flow cytometry for assessing minor leukemic populations. 相似文献
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To determine the type and proportion of cases within that type of acute lymphoblastic leukemia (ALL) that has a natural killer (NK) cell phenotype, we examined leukemic blasts from 31 children with ALL (14 with T-ALL, 17 with non-T-ALL) for expression of antigens detected by NK-specific monoclonal antibodies Leu 11b, Leu 7, and 1G2 (an antibody we have developed that cross-reacts with Leu 7). None of the patients had leukemic blasts that reacted with Leu 11b. However, leukemic blasts from four T-ALL patients were 1G2+ and/or Leu 7+. Blasts from two of these had spontaneous lytic activity against standard NK target cell line K562; blasts from one killed K562 only when incubated with interferon; blasts from the other had no lytic activity against K562 but did manifest antibody-dependent cell-mediated cytotoxicity against antibody-coated cells from NK-resistant cell line SB. Blasts from all four Leu 7+ patients had L2 morphology. In one, the leukemic blasts had azurophilic cytoplasmic granules similar to those found in NK-enriched normal populations of large granular lymphocytes. These findings suggest that a significant proportion of T-cell acute lymphoblastic leukemias may be malignancies of NK cell origin. 相似文献
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