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1.
Int J Hematol ; 111(1): 75-83, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31686349

RESUMEN

Expression of intragenic exon rearrangements (IERs) has reportedly been detected in both normal and cancer cells. However, there have been few reports of occurrence of these rearrangements specific to neoplasms including malignant lymphoma. In this study, we detected IERs of ten genes (NBPF8, SOBP, AUTS2, RAB21, SPATA13, ABCC4, WDR7, PHLPP1, NFATC1 and MAGED1) in non-Hodgkin B cell lymphoma (B-NHL) cell line KPUM-UH1 using a high-resolution single nucleotide polymorphism array and reverse transcription polymerase chain reaction using reversely directed divergent primers within exons involved in genomic intragenic gains followed by sequencing analysis. Among them, the IERs involved in SOBP (6q21) exon 2 and 3 and AUTS2 (7q11.22) exon 2-4 were the molecular lesions specific to tumors and were frequently detected in B-NHL samples. These IERs constitute novel genetic alterations of B-NHL, which might be associated with tumorigenesis and be useful as genetic biological markers.

3.
Artículo en Inglés | MEDLINE | ID: mdl-31789783

RESUMEN

We have experienced 3 consecutive cases of familial hemophagocytic lymphohistiocytosis (FHL). All affected infants had mutations in exon 3 of the perforin gene. The first had a homozygous mutation, c.1168C>T (p.R390*), caused by maternal uniparental isodisomy. The second and third had compound heterozygous mutations: c.781G>A (p.E261K) and c.1491T>A (p.C497*); c.1724G>T (p.C242G) and p.R390*, respectively. FHL is very rare in Northern Japan but should be suspected if infants exhibit prolonged fever. This is the first report of a relationship of p.R390* with FHL caused by uniparental isodisomy, and the second reported case of FHL type 2 with this form of inheritance.

4.
Br J Haematol ; 2019 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-31612466

RESUMEN

Although infants (age <1 year) with acute myeloid leukaemia (AML) have unique characteristics and are vulnerable to chemotherapy, children aged 1-2 years with AML may have characteristics similar to that of infants. Thus, we analysed 723 paediatric AML patients treated on the Japanese AML99 and AML-05 trials to identify characteristics of younger children. We identified patients aged <3 years (the younger group) as a distinct subgroup. KMT2A-rearrangement (KMT2A-R), CBFA2T3-GLIS2, CBFB-MYH11 and NUP98-KDM5A were frequently found in the younger group. Prognostic analyses revealed poor 5-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) in patients with CBFA2T3-GLIS2 (42%, 17% and 83%, respectively) and those with NUP98-KDM5A (33%, 17% and 83%, respectively). Additionally, we identified KMT2A-R and CBFB-MYH11 as age-specific prognostic markers. Regarding KMT2A-R, the younger group had significantly better OS, EFS and CIR than the older group (aged 3 to <18 years) (P = 0·023, 0·011 and <0·001, respectively). Conversely, concerning CBFB-MYH11, the younger group had significantly poor EFS and CIR than the older group (each P < 0·001), suggesting that certain molecular markers are linked to different prognoses according to age. Therefore, we characterized patients <3 years as a distinct subgroup of paediatric AML.

5.
Blood Adv ; 3(20): 3157-3169, 2019 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-31648321

RESUMEN

Recent advances in the genetic understanding of acute myeloid leukemia (AML) have improved clinical outcomes in pediatric patients. However, ∼40% of patients with pediatric AML relapse, resulting in a relatively low overall survival rate of ∼70%. The objective of this study was to reveal the comprehensive genetic background of pediatric AML. We performed transcriptome analysis (RNA sequencing [RNA-seq]) in 139 of the 369 patients with de novo pediatric AML who were enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 trial and investigated correlations between genetic aberrations and clinical information. Using RNA-seq, we identified 54 in-frame gene fusions and 1 RUNX1 out-of-frame fusion in 53 of 139 patients. Moreover, we found at least 258 gene fusions in 369 patients (70%) through reverse transcription polymerase chain reaction and RNA-seq. Five gene rearrangements were newly identified, namely, NPM1-CCDC28A, TRIP12-NPM1, MLLT10-DNAJC1, TBL1XR1-RARB, and RUNX1-FNBP1. In addition, we found rare gene rearrangements, namely, MYB-GATA1, NPM1-MLF1, ETV6-NCOA2, ETV6-MECOM, ETV6-CTNNB1, RUNX1-PRDM16, RUNX1-CBFA2T2, and RUNX1-CBFA2T3. Among the remaining 111 patients, KMT2A-PTD, biallelic CEBPA, and NPM1 gene mutations were found in 11, 23, and 17 patients, respectively. These mutations were completely mutually exclusive with any gene fusions. RNA-seq unmasked the complexity of gene rearrangements and mutations in pediatric AML. We identified potentially disease-causing alterations in nearly all patients with AML, including novel gene fusions. Our results indicated that a subset of patients with pediatric AML represent a distinct entity that may be discriminated from their adult counterparts. Based on these results, risk stratification should be reconsidered.

6.
Pediatr Int ; 61(11): 1103-1108, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31519067

RESUMEN

BACKGROUND: Ploidy is a highly significant prognostic factor for pediatric acute lymphoblastic leukemia (ALL). Children with hypodiploid ALL have poor outcomes despite current intensive chemotherapy. Little has been investigated with regard to hypodiploid ALL in Japanese children. METHODS: We retrospectively collected clinical data on hypodiploid ALL cases from the registries of prospective multicenter trials conducted by the four independent clinical study groups in Japan between 1997 and 2012. RESULTS: A total of 117 ALL patients with hypodiploidy were analyzed in this study. There were 101, eight, and eight patients with 45, 44, and fewer than 44 chromosomes, respectively. The 5 year overall survival rates differed significantly: 86.0%, 87.5%, and 62.5% for patients with 45, 44, and fewer than 44 chromosomes, respectively (P = 0.037). Of the eight patients with 44 chromosomes, seven were alive, including five patients who maintained complete remission without undergoing hematopoietic stem cell transplantation (HSCT). Of the eight patients with fewer than 44 chromosomes, six were good responders to prednisolone and none had induction failure, but the relapse rate was high (5/8). No patients had central nervous system relapse. Four patients underwent HSCT after relapse, but only one survived. CONCLUSIONS: Outcomes of Japanese ALL patients with fewer than 44 chromosomes were poor, as previously reported in other countries. Although the sample size was small, patients with 44 chromosomes had better prognoses than those previously reported. Further studies including international collaboration are needed to improve outcomes for pediatric ALL patients with fewer than 44 chromosomes.

7.
Int J Hematol ; 108(4): 438-442, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-29971602

RESUMEN

Myeloid sarcoma (MS) is a rare neoplastic condition that is often described in association with acute myeloid leukemia (AML). MS in childhood has received little attention, particularly in Japan. We carried out a nationwide retrospective analysis of Japanese children diagnosed with MS without bone marrow involvement. Inclusion criteria were diagnosis of MS at younger than 20 years of age between January 1, 2000 and December 31, 2013. There was a predominance of males (8:2), and the median age at MS diagnosis was 4 years. Sites of involvement varied and included skin (n = 3), head and/or neck (n = 2), and multiple sites (n = 2). Karyotypes were evaluated in seven patients, with one individual carrying t(8;21) and t(9;11). Four patients developed bone marrow involvement 2-55 months after diagnosis of MS. All patients received chemotherapy for de novo AML and two individuals received HSCT in first remission. Seven of ten patients survived for 50-152 months (median, 93 months) without disease after initial chemotherapy. This retrospective study confirmed that pediatric MS without bone marrow involvement in Japan is a very rare disease. MS patients responded favorably to therapies for de novo AML, and HSCT in first remission was not indicated for all patients.


Asunto(s)
Médula Ósea/patología , Sarcoma Mieloide , Cariotipo Anormal , Adolescente , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Japón/epidemiología , Masculino , Sarcoma Mieloide/diagnóstico , Sarcoma Mieloide/tratamiento farmacológico , Sarcoma Mieloide/mortalidad , Sarcoma Mieloide/patología , Tasa de Supervivencia
8.
Int J Hematol ; 108(1): 91-97, 2018 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-29574603

RESUMEN

Therapy-related leukemia (t-leukemia) is associated with dismal prognosis. Published pediatric t-leukemia data are somewhat outdated and may not reflect recent advances in treatment. We report a retrospective nationwide survey of patients diagnosed between 2000 and 2013 in Japan. We identified 43 patients with pediatric t-leukemia; 33 had t-acute myeloid leukemia (t-AML), eight had t-acute lymphoblastic leukemia (t-ALL) and two had t-acute undifferentiated leukemia. Median age at onset and latency were 12 years and 3.8 years, respectively, consistent with previous reports. Of t-AML patients, 63.6% harbored topoisomerase II inhibitor (topo II)-related genetic abnormalities, while only 12.5% of t-ALL patients had such alterations, suggesting that topo II is not key to t-ALL leukemogenesis. The 7-year overall survival (OS) for all 43 patients was 39.2 ± 11.6%. The 5-year OS was 50 ± 20.4% in t-ALL, and 55.2 ± 11.0% in t-AML. Allogeneic hematopoietic cell transplantation (allo-HCT) was associated with superior 5-year OS (HCT(+) vs. HCT(-), 78.8 vs. 12.1%; p < 0.001), and 26 of 32 patients received allo-HCT in complete remission (CR). Only allo-HCT was associated with superior OS on multivariate analysis (HR 0.003, 95% CI 0.0001-0.098; p < 0.001). These findings suggest that allo-HCT in CR improves pediatric t-leukemia outcomes.


Asunto(s)
Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Edad de Inicio , Aloinjertos , Niño , Preescolar , ADN-Topoisomerasas de Tipo II/genética , Femenino , Trasplante de Células Madre Hematopoyéticas , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Japón , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Proteína de la Leucemia Mieloide-Linfoide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Pronóstico , Estudios Retrospectivos , Encuestas y Cuestionarios , Tasa de Supervivencia , Factores de Tiempo , Inhibidores de Topoisomerasa II
10.
Br J Haematol ; 178(4): 534-546, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28439875

RESUMEN

Cytogenetic/molecular heterogeneity is the hallmark of multiple myeloma (MM). However, we recently showed that the serine/threonine kinase PDPK1 and its substrate RPS6KA3 (also termed RSK2) are universally active in MM, and play pivotal roles in myeloma pathophysiology. In this study, we assessed involvement of aberrant miR-375 repression in PDPK1 overexpression in MM. An analysis of plasma cells from 30 pre-malignant monoclonal gammopathies of undetermined significance and 73 MM patients showed a significant decrease in miR-375 expression in patient-derived plasma cells regardless of the clinical stage, compared to normal plasma cells. Introduction of miR-375 reduced PDPK1 expression in human myeloma cell lines (HMCLs), indicating that miR-375 is the dominant regulator of PDPK1 expression. In addition, miR-375 introduction also downregulated IGF1R and JAK2 in HMCLs. CpG islands in the MIR375 promoter were pathologically hypermethylated in all 8 HMCLs examined and in most of 58 patient-derived myeloma cells. Treatment with SGI-110, a hypomethylating agent, and/or trichostatin A, a histone deacetylase inhibitor, increased miR-375 expression, but repressed PDPK1, IGF1R and JAK2 in HMCLs. Collectively, these results show the universal involvement of overlapping epigenetic dysregulation for abnormal miR-375 repression in MM, which is likely to contribute to myelomagenesis and to subsequent myeloma progression by activating oncogenic signalling pathways.


Asunto(s)
Proteínas Quinasas Dependientes de 3-Fosfoinosítido/metabolismo , Represión Epigenética/genética , MicroARNs/genética , Mieloma Múltiple/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Línea Celular Tumoral , Islas de CpG/genética , Metilación de ADN , Epigénesis Genética , Humanos , MicroARNs/biosíntesis , Gammopatía Monoclonal de Relevancia Indeterminada/genética , Mieloma Múltiple/metabolismo , Proteínas de Neoplasias/metabolismo , Células Plasmáticas/metabolismo , Recurrencia , Transducción de Señal/genética , Sindecano-1/sangre
11.
Genes Chromosomes Cancer ; 56(5): 394-404, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28063190

RESUMEN

Pediatric acute megakaryoblastic leukemia in non-Down syndrome (AMKL) is a unique subtype of acute myeloid leukemia (AML). Novel CBFA2T3-GLIS2 and NUP98-KDM5A fusions recurrently found in AMKL were recently reported as poor prognostic factors. However, their detailed clinical and molecular characteristics in patients treated with recent improved therapies remain uncertain. We analyzed molecular features of 44 AMKL patients treated on two recent Japanese AML protocols, the AML99 and AML-05 trials. We identified CBFA2T3-GLIS2, NUP98-KDM5A, RBM15-MKL1, and KMT2A rearrangements in 12 (27%), 4 (9%), 2 (5%), and 3 (7%) patients, respectively. Among 459 other AML patients, NUP98-KDM5A was identified in 3 patients, whereas CBFA2T3-GLIS2 and RBM15-MKL1 were only present in AMKL. GATA1 mutations were found in 5 patients (11%). Four-year overall survival (OS) and event-free survival (EFS) rates of CBFA2T3-GLIS2-positive patients in AMKL were 41.7% and 16.7%, respectively. Three-year cumulative incidence of relapse in CBFA2T3-GLIS2-positive patients was significantly higher than that of CBFA2T3-GLIS2-negative patients (75.0% vs. 35.7%, P = 0.024). In multivariate analyses, CBFA2T3-GLIS2 was an independent poor prognostic factor for OS (HR, 4.34; 95% CI, 1.31-14.38) and EFS (HR, 2.95; 95% CI, 1.20-7.23). Furthermore, seven (54%) of 13 infant AMKL patients were CBFA2T3-GLIS2-positive. Notably, out of 7 CBFA2T3-GLIS2-positive infants, six (86%) relapsed and five (71%) died. Moreover, all of CBFA2T3-GLIS2-positive patients who experienced induction failure (n = 3) were infants, indicating worse prognosis of CBFA2T3-GLIS2-positive infants. These findings indicated the significance of CBFA2T3-GLIS2 as a poor prognostic factor in AMKL patients, particularly in infants.


Asunto(s)
Biomarcadores de Tumor/genética , Síndrome de Down/genética , Leucemia Megacarioblástica Aguda/genética , Mutación/genética , Proteínas de Fusión Oncogénica/genética , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Humanos , Lactante , Recién Nacido , Leucemia Megacarioblástica Aguda/patología , Masculino , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia
12.
Oncol Lett ; 13(1): 215-221, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-28123544

RESUMEN

Several novel fusion transcripts were identified by next-generation sequencing in gastric cancer; however, the breakpoint junctions have yet to be characterized. The present study characterized a plethora of APIP-FGFR2 genomic breakpoints in the SNU-16 gastric cancer cell line, which harbored homogeneously staining regions (hsrs) and double minute chromosomes. Oligonucleotide microarrays revealed high-level amplifications at chromosomes 8q24.1 (0.8 Mb region), 10q26 (1.1 Mb) and 11p13 (1.1 Mb). These amplicons contained MYC and PVT1 at chromosome 8q24.1, BRWD2, FGFR2 and ATE1 at chromosome 10q26, and 24 genes, including APIP, CD44, RAG1 and RAG2, at chromosome 11p13. Based on these findings, reverse transcription-polymerase chain reaction (PCR) was performed using various candidate gene primers to detect possible fusion transcripts, and several products using primer sets for the APIP and FGFR2 genes were detected. Eventually, three in-frame and two out-of-frame fusion transcripts were detected. Notably, PCR analysis of the entire genomic DNA detected three distinct genomic junctions. The breakpoints were within intron 5 of APIP, which contained three distinct breakpoints, and introns 5, 7 and 9 of FGFR2. Fluorescence in situ hybridization showed several fusion signals within hsrs using two short probes (~10-kb segments of a bacterial artificial chromosome clone) containing exons 2-5 of APIP or exons 11-13 of FGFR2. Although, for any given fusion, a multiplicity of transcripts is thought to be created by alternative splicing of one rearranged allele, the results of the present study suggested that genomic fusions of APIP and FGFR2 are generated in hsrs with a diversity of breakpoints that are then faithfully transcribed.

13.
Pediatr Blood Cancer ; 63(8): 1394-9, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27135782

RESUMEN

BACKGROUND: Overexpression of CXC chemokine receptor 4 (CXCR4+) is a poor prognostic factor in adult acute myeloid leukemia (AML); however, its prognostic significance in pediatric AML is unclear. PROCEDURE: This retrospective study examined the prognostic significance of CXCR4+ in pediatric AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. RESULTS: In the total cohort (n = 248), no significant differences were observed between CXCR4+ patients (n = 81) and CXCR4- patients (n = 167) in terms of 3-year overall survival (OS) (69.4% vs. 75.2%, P = 0.44). However, there was a significant difference in 3-year OS between CXCR4+ and CXCR4- patients in the low-risk (LR) group (n = 93; 79.2% vs. 98.3%, P = 0.007). CXCR4+ patients in the t(8;21) AML without KIT mutation group had a significantly worse 3-year OS than CXCR4- patients (n = 44; 76.1% vs. 100.0%, P = 0.01). Multivariate Cox regression analysis identified CXCR4+ as a poor prognostic factor for OS in LR AML patients (hazard ratio, 11.47; P = 0.01). Consistent with the data for survival analysis, CXCR4+ patients in the t(8;21) AML group had a higher incidence of splenomegaly than CXCR4- patients (25.9% vs. 5.9%, P = 0.03). CONCLUSIONS: These results suggest that CXCR4+ is a poor prognostic factor for LR patients, particularly t(8;21) patients without KIT mutation. The poor outcome was only applicable to OS, not relapse-free survival (RFS); thus, CXCR4+ may be associated with a poor prognosis after recurrence. Intensive therapy, including administration of CXCR4 antagonists, may be promising for pediatric AML patients with LR.


Asunto(s)
Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Receptores CXCR4/biosíntesis , Adolescente , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Japón , Masculino , Mutación , Pronóstico , Proteínas Proto-Oncogénicas c-kit/genética , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/genética , Estudios Retrospectivos , Esplenomegalia/patología , Análisis de Supervivencia
14.
Br J Haematol ; 174(3): 437-43, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27029412

RESUMEN

We evaluated the efficacy of treatment using reduced cumulative doses of anthracyclines in children with acute promyelocytic leukaemia (APL) in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-P05 study. All patients received two and three subsequent courses of induction and consolidation chemotherapy respectively, consisting of all-trans retinoic acid (ATRA), cytarabine and anthracyclines, followed by maintenance therapy with ATRA. Notably, a single administration of anthracyclines was introduced in the second induction and all consolidation therapies to minimize total doses of anthracycline. The 3-year event-free (EFS) and overall survival rates for 43 eligible children were 83·6% [95% confidence interval (CI): 68·6-91·8%] and 90·7% (95% CI: 77·1-96·4%), respectively. Although two patients died of intracranial haemorrhage or infection during induction phases, no cardiac adverse events or treatment-related deaths were observed during subsequent phases. Patients not displaying M1 marrow after the first induction therapy, or those under 5 years of age at diagnosis, showed inferior outcomes (3-year EFS rate; 33·3% (95% CI: 19·3-67·6%) and 54·6% (95% CI: 22·9-78·0%), respectively). In conclusion, a single administration of anthracycline during each consolidation phase was sufficient for treating childhood APL. In younger children, however, conventional ATRA and chemotherapy may be insufficient so that alternative therapies should be considered.


Asunto(s)
Antraciclinas/administración & dosificación , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/mortalidad , Adolescente , Niño , Preescolar , Quimioterapia de Consolidación/métodos , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Humanos , Quimioterapia de Inducción/métodos , Lactante , Japón , Leucemia Promielocítica Aguda/complicaciones , Quimioterapia de Mantención/métodos , Masculino , Estudios Prospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Tretinoina/administración & dosificación
15.
Pediatr Blood Cancer ; 63(2): 248-54, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26481183

RESUMEN

BACKGROUND: On the basis of results of previous Japanese trials for myeloid leukemia in Down syndrome (ML-DS), the efficacy of risk-oriented therapy was evaluated in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-D05 study. PROCEDURE: All patients received induction chemotherapy that consisted of pirarubicin, intermediate-dose cytarabine, and etoposide. Patients who achieved complete remission (CR) after initial induction therapy were stratified to the standard risk (SR) group and received four courses of reduced-dose intensification therapy. Patients who did not achieve CR were stratified to the high risk (HR) group and received intensified therapy that consisted of continuous or high-dose cytarabine. RESULTS: A total of 72 patients were eligible and evaluated. One patient died of sepsis during initial induction therapy. Sixty-nine patients were stratified to SR and two patients to HR. No therapy-related deaths were observed during intensification therapy. The 3-year event-free and overall survival rates were 83.3% ± 4.4% and 87.5% ± 3.9%, respectively. Age at diagnosis less than 2 years was a significant favorable prognostic factor for risk of relapse (P = 0.009). CONCLUSIONS: The attempt of risk-oriented prospective study for ML-DS was unsuccessful, but despite the dose reduction of chemotherapeutic agents, the overall outcome was good, and further dose reduction might be possible for specific subgroups.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Síndrome de Down/complicaciones , Leucemia Mieloide/complicaciones , Leucemia Mieloide/tratamiento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Preescolar , Citarabina/administración & dosificación , Citarabina/efectos adversos , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/análogos & derivados , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Humanos , Quimioterapia de Inducción/métodos , Lactante , Japón , Estimación de Kaplan-Meier , Leucemia Mieloide/mortalidad , Masculino , Estudios Prospectivos
17.
Genes Chromosomes Cancer ; 54(12): 788-95, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26390996

RESUMEN

The deleted in colorectal carcinoma (DCC) gene at 18q21 encodes a netrin-1 receptor, a tumor suppressor that prevents cell growth. While allele loss or decreased expression of DCC has been associated with the progression of solid tumors and hematologic malignancies, including leukemias and malignant lymphomas, its involvement has not been evaluated in multiple myeloma (MM), a plasma cell malignancy characterized by complex and heterogenous molecular abnormalities. We here show that 10 of 11 human myeloma-derived cell lines (HMCLs) expressed non-translated aberrant DCC transcriptional variants, in which exon 2 fuses with intron 1 instead of exon 1 (mt.DCC). Among them, two co-expressed wild type transcripts (wt.DCC), while eight co-expressed the splicing variant (sv.DCC) lacking exon 1. The remaining HMCL expressed only sv.DCC. In addition, analyses revealed that there were two types of mt.DCC that differed in their fusion of intron 1 with exon 2. In patient-derived samples from 30 MM and 8 monoclonal gammopathy of undetermined significance (MGUS) patients, wt.DCC was expressed in 53% of MM, but not in MGUS, while 23% of MM and 75% of MGUS expressed only sv.DCC. Considering that 25% of MGUS, 57% of MM, and 91% HMCLs expressed mt.DCC, our results suggest that the acquisition of mt.DCC might be a secondary genetic change in plasma cell dyscrasia.


Asunto(s)
Genes Supresores de Tumor , Gammopatía Monoclonal de Relevancia Indeterminada/genética , Mieloma Múltiple/genética , Receptores de Superficie Celular/genética , Proteínas Supresoras de Tumor/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Biomarcadores de Tumor/metabolismo , Caspasas/metabolismo , Línea Celular Tumoral , Cromosomas Humanos Par 18/genética , Receptor DCC , Proteínas de Unión al ADN/metabolismo , Progresión de la Enfermedad , Regulación hacia Abajo , Exones , Humanos , Intrones , Pérdida de Heterocigocidad , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptores de Superficie Celular/metabolismo , Proteína Smad4/metabolismo , Sindecano-1/genética , Factor de Transcripción 4 , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo
18.
Pediatr Blood Cancer ; 62(11): 2021-4, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26138905

RESUMEN

Myeloid malignancy with Down syndrome (ML-DS) is estimated to have a step-wise leukemogenesis including GATA1 mutation. Trisomy 21 is essential for ML-DS; however, we do not know exactly which gene or genes located on chromosome 21 are necessary for the ML-DS. We report a female infant with transient myeloproliferative disorder (TMD) and partial trisomy 21. SNP array analysis showed 10 Mb amplification of 21q22.12-21q22.3, which included DYRK1A, ERG, and ETS but not the RUNX1 gene. With two other reported TMD cases having partial trisomy 21, DYRK1A, ERG, and ETS were the most likely genes involved in collaboration with the GATA1 mutation.


Asunto(s)
Cromosomas Humanos Par 21/genética , Síndrome de Down/genética , Trastornos Mieloproliferativos/genética , Polimorfismo de Nucleótido Simple , Síndrome de Down/complicaciones , Femenino , Factor de Transcripción GATA1/genética , Humanos , Lactante , Trastornos Mieloproliferativos/complicaciones , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas c-ets/genética , Transactivadores/genética , Regulador Transcripcional ERG
19.
Genes Chromosomes Cancer ; 54(7): 409-17, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25930743

RESUMEN

Acute lymphoblastic leukemia (ALL) occasionally develops before or after the onset of Langerhans cell histiocytosis (LCH). The mechanism of LCH developing after ALL remains unclear; thus the clonality of LCH developing during maintenance chemotherapy for T-cell ALL (T-ALL) was investigated. The T-ALL and LCH cells tested had the same T-cell receptor (TCR) gamma rearrangement. Mutation analysis of the NOTCH1 gene revealed 7213C>T (Q2405X) in exon 34 in T-ALL and LCH cells, but 5156T>C (I1719T) in exon 27 only in T-ALL. Polymerase chain reaction-restriction fragment length polymorphism analysis revealed three patterns of NOTCH1 mutations in T-ALL cells. The results suggest that the T-ALL and LCH cells were derived from a common precursor with TCR rearrangement and a single NOTCH1 mutation, rather than LCH cells developing from a minor clone of T-ALL with single NOTCH1 mutation.


Asunto(s)
Histiocitosis de Células de Langerhans/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptor Notch1/genética , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Antineoplásicos/efectos adversos , Niño , Células Clonales/patología , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Humanos , Células de Langerhans/patología , Leucocitosis/genética , Masculino , Mutación , Linfocitos T/patología , Trombocitopenia/genética
20.
Genes Chromosomes Cancer ; 54(7): 401-8, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25951811

RESUMEN

We have identified a novel SPAG9-JAK2 fusion in a B-cell precursor acute lymphoblastic leukemia (ALL) with t(9;17)(p24;q21) and a poor outcome, using paired-end transcriptome sequencing. Homozygous and hemizygous deletions of CDKN2A/2B, and hemizygous deletions of PAX5, BTG1, CDK6, ADARB2, and IKZF1 were also identified by multiple ligation-dependent probe amplification and single nucleotide polymorphism array analyses. Having both a tyrosine kinase-activating rearrangement and genomic lesions affecting lymphoid transcription factors suggested that the leukemia was of the Philadelphia chromosome (Ph)/BCR-ABL1-like ALL subtype and that JAK2 inhibitors might be able to overcome this aggressive ALL with SPAG9-JAK2.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Fusión Génica , Janus Quinasa 2/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Linfocitos B/patología , Cromosomas Humanos Par 17 , Humanos , Leucocitosis/genética , Masculino , Cromosoma Filadelfia , Polimorfismo de Nucleótido Simple , Trombocitopenia/genética , Factores de Transcripción/genética , Transcriptoma
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