RESUMEN
ABSTRACT: Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing. Sixteen novel mutational targets were identified in ML-DS samples. Of these, inactivations of IRX1 (16.2%) and ZBTB7A (13.2%) were commonly implicated in the upregulation of the MYC pathway and were potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors. Partial tandem duplications of RUNX1 on chromosome 21 were also found, specifically in ML-DS samples (13.7%), presenting its essential role in DS leukemia progression. Finally, in 177 patients with ML-DS treated following the same ML-DS protocol (the Japanese Pediatric Leukemia and Lymphoma Study Group acute myeloid leukemia -D05/D11), CDKN2A, TP53, ZBTB7A, and JAK2 alterations were associated with a poor prognosis. Patients with CDKN2A deletions (n = 7) or TP53 mutations (n = 4) had substantially lower 3-year event-free survival (28.6% vs 90.5%; P < .001; 25.0% vs 89.5%; P < .001) than those without these mutations. These findings considerably change the mutational landscape of ML-DS, provide new insights into the mechanisms of progression from TAM to ML-DS, and help identify new therapeutic targets and strategies for ML-DS.
Asunto(s)
Síndrome de Down , Mutación , Humanos , Síndrome de Down/genética , Síndrome de Down/complicaciones , Masculino , Femenino , Reacción Leucemoide/genética , Lactante , Preescolar , Secuenciación del Exoma , Pronóstico , Leucemia Mieloide/genética , Recién Nacido , Niño , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genéticaRESUMEN
Diamond-Blackfan anemia (DBA) is a congenital anemia with erythroid cell aplasia. Most of the causative genes are ribosomal proteins. GATA1, a hematopoietic master transcription factor required for erythropoiesis, also causes DBA. GATA1 is located on Xp11.23; therefore, DBA develops only in males in an X-linked inheritance pattern. Here, we report a case of transient erythroblastopenia and moderate anemia in a female newborn infant with a de novo GATA1 variant. In this patient, increased methylation of the GATA1 wild-type allele was observed in erythroid cells. Skewed lyonization of GATA1 may cause mild transient erythroblastopenia in a female patient.
Asunto(s)
Anemia Aplásica , Anemia de Diamond-Blackfan , Anemia Hemolítica Congénita , Masculino , Lactante , Recién Nacido , Humanos , Femenino , Proteínas Ribosómicas/genética , Anemia de Diamond-Blackfan/genética , Eritropoyesis , Factor de Transcripción GATA1/genéticaRESUMEN
Hypomethylating agent treatment for myeloid leukemia associated with Down syndrome (ML-DS) has been scarcely reported. Herein, we collected information on azacitidine treatment for ML-DS in Japan. Forty-eight cycles of azacitidine treatment were performed for 12 patients, including 11 relapsed or refractory (R/R) patients. In 40 cycles, azacitidine was used as monotherapy. No azacitidine-related death was observed. One cycle concurrently administered with methotrexate-based intrathecal therapy was discontinued due to toxicities. Only 4 of the 19 cycles given in non-remission achieved complete or partial remission. In conclusion, although most toxicities were acceptable, azacitidine monotherapy might be insufficient for R/R ML-DS cases.
Asunto(s)
Antimetabolitos Antineoplásicos , Azacitidina , Síndrome de Down , Leucemia Mieloide , Humanos , Síndrome de Down/complicaciones , Síndrome de Down/tratamiento farmacológico , Azacitidina/uso terapéutico , Azacitidina/efectos adversos , Masculino , Femenino , Estudios Retrospectivos , Antimetabolitos Antineoplásicos/uso terapéutico , Antimetabolitos Antineoplásicos/efectos adversos , Japón/epidemiología , Preescolar , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/complicaciones , Niño , Adolescente , Lactante , AdultoRESUMEN
BACKGROUND: In addition to regulating the antiviral response, increased expression of Toll-like receptor 3 (TLR3) in resident renal cells plays a role in developing some forms of glomerulonephritis. TLR3 activation leads to type I interferon (IFN) production, which induces the expression of IFN-stimulated genes (ISGs). However, the role of ISG20 expression in resident renal cells remains unclear. METHODS: Cultured normal human glomerular endothelial cells (GECs) were treated with polyinosinic-polycytidylic acid (poly IC), Escherichia coli lipopolysaccharide (LPS), R848, and CpG (TLR3, TLR4, TLR7, and TLR9 agonists, respectively). The mRNA levels of ISG20, CX3CL1/fractalkine, and CXCL10/IP-10 were measured by quantitative reverse transcription-polymerase chain reaction. ISG20 protein expression was assessed by Western blotting. RNA interference was used to knockdown IFN-ß and ISG20 expression. CX3CL1 protein levels were assessed by enzyme-linked immunosorbent assay. We performed immunofluorescence to examine endothelial ISG20 expression in biopsy specimens from patients with lupus nephritis (LN). RESULTS: In GECs, the expression of ISG20 mRNA and protein was increased by polyIC, not by LPS, R848, or CpG treatment. Moreover, ISG20 knockdown prevented poly IC-induced CX3CL1 expression but had no effect on CXCL10 expression. Intense endothelial ISG20 immunoreactivity was observed in biopsy specimens obtained from patients with proliferative LN. CONCLUSION: In GECs, ISG20 was regulated via TLR3 but not via TLR4, TLR7, or TLR9 signaling. Moreover, ISG20 was involved in regulating CX3CL1 production. In addition to regulating antiviral innate immunity, ISG20 may act as a mediator of CX3CL1 production, thereby inducing glomerular inflammation, particularly in patients with LN.
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Exorribonucleasas , Nefritis Lúpica , Humanos , Antivirales , Factores de Restricción Antivirales , Células Cultivadas , Células Endoteliales/metabolismo , Lipopolisacáridos/farmacología , Células Mesangiales , Poli I-C/farmacología , ARN Mensajero/genética , Receptor Toll-Like 3/genética , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 9/metabolismo , Exorribonucleasas/genéticaRESUMEN
The purpose of this study is to establish a treatment with appropriate intensity for children (<16 years old at diagnosis) with de novo acute myeloid leukemia (excluding acute promyelocytic leukemia and myeloid leukemia associated with Down syndrome) according to a risk stratification based on recurrent leukemic cytogenetic abnormalities and flow-cytometric minimal residual disease at end of initial induction chemotherapy and to validate the safety and efficacy of gemtuzumab ozogamicin (GO)-combined post-induction chemotherapy for the non-low-risk (non-LR) patients. The primary endpoint of this phase III study is three-year disease-free survival rate, which will be compared between the GO and non-GO arms of the non-LR (intermediate-risk and high-risk [HR]) patients. All HR patients will be allocated to allogeneic hematopoietic stem cell transplantation in first remission. This trial has been registered at the Japan Registry of Clinical Trials (jRCTs041210015).
Asunto(s)
Quimioterapia de Inducción , Leucemia Mieloide Aguda , Adolescente , Aminoglicósidos/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Gemtuzumab , Humanos , Neoplasia Residual/tratamiento farmacológico , Medición de RiesgoRESUMEN
We report a female newborn with acute myelogenous leukemia (AML) associated with a MYB-GATA1 fusion gene. Morphologic findings of myeloid lineage were obtained using light microscopy. Cytogenetic analysis of peripheral blood showed a complex karyotype: 46,X,-X,add(3)(q21),der(6)add(6)(q21)del(6)(q?), +mar1[5]/46,XX[15]. Targeted RNA sequencing revealed a MYB-GATA1 fusion gene. Reduced-dose AML-type chemotherapy resulted in remission and survival for >3 years without relapse. The present case demonstrated the feasibility of carrying out targeted RNA sequencing for identifying MYB-GATA1 and supports the notion that neonatal AML with MYB-GATA1 with reduced chemotherapy may show better prognosis than other highly toxic therapies.
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Aberraciones Cromosómicas , Factor de Transcripción GATA1/genética , Enfermedades del Recién Nacido , Leucemia Mieloide Aguda , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas c-myb/genética , Femenino , Humanos , Recién Nacido , Enfermedades del Recién Nacido/tratamiento farmacológico , Enfermedades del Recién Nacido/genética , Leucemia Mieloide Aguda/congénito , Leucemia Mieloide Aguda/tratamiento farmacológicoRESUMEN
Extraneural recurrence of a medulloblastoma is rare with dismal prognosis. A 9-year-old girl with medulloblastoma was treated with gross total resection followed by a combination of chemotherapy and radiotherapy. Fourteen months after treatment completion, she developed multifocal bone metastases. Despite chemotherapy combined with irradiation, she died 18 months after recurrence due to progressive disease. Fluorescence in situ hybridization on formalin-fixed paraffin-embedded tissue sections revealed MYCN amplification and TP53 loss, consistent with the genetic alterations of a rapidly progressive subgroup of recurrent medulloblastomas. In clinical practice, dismal biologic features can be determined using fluorescence in situ hybridization in defective materials.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , Neoplasias Encefálicas/patología , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/terapia , Niño , Femenino , Humanos , Hibridación Fluorescente in Situ , Meduloblastoma/genética , Meduloblastoma/patología , Meduloblastoma/terapia , Proteína Proto-Oncogénica N-Myc/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: Dysregulation of the coagulation fibrinolysis system in resident glomerular cells is associated with the pathogenesis of lupus nephritis. However, the role of plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) in resident glomerular cells remains undetermined. METHODS: We examined the expression of PAI-1 and tPA mRNA in cultured normal human glomerular endothelial cells (GECs) treated with serum from patients with systemic lupus erythematosus (SLE) using quantitative reverse transcription polymerase chain reactions. We determined the relationship between PAI-1/tPA mRNA expression and several clinical/laboratory parameters. Serum from 16 patients (nine patients with new-onset SLE and seven patients with stable SLE) was used in the study. RESULTS: Plasminogen activator inhibitor-1 and tPA mRNA expression was significantly higher in GECs treated with serum of patients with new-onset SLE than other groups. The PAI-1 and tPA mRNA levels were also significantly correlated in GECs treated with serum from patients with SLE. Interestingly, both PAI-1 and tPA mRNA levels in GECs were inversely correlated with serum C4 level and positively correlated with SLE disease activity. CONCLUSIONS: These results suggest that serum from patients with SLE may activate the fibrinolysis system in glomerulus, which may be involved in the pathogenesis of lupus nephritis.
Asunto(s)
Lupus Eritematoso Sistémico , Nefritis Lúpica , Células Endoteliales/metabolismo , Células Endoteliales/patología , Fibrinólisis , Humanos , Lupus Eritematoso Sistémico/complicaciones , Nefritis Lúpica/complicaciones , Nefritis Lúpica/metabolismo , Nefritis Lúpica/patología , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismo , ARN Mensajero/genética , Activador de Tejido Plasminógeno/genética , Activador de Tejido Plasminógeno/metabolismoRESUMEN
BACKGROUND: Sustained type I interferon (IFN) activation via Toll-like receptor (TLR) 3, 7 and 9 signaling has been reported to play a pivotal role in the development of lupus nephritis (LN). Although type I IFN activation has been shown to induce interferon-stimulated genes (ISGs) expression in systemic lupus erythematosus, the implication of ISGs expression in intrinsic glomerular cells remains largely unknown. METHODS: We treated cultured human glomerular endothelial cells (GECs) with polyinosinic-polycytidylic acid (poly IC), R848, and CpG (TLR3, TLR7, and TLR9 agonists, respectively) and analyzed the expression of DExD/H-Box Helicase 60 (DDX60), a representative ISG, using quantitative reverse transcription-polymerase chain reaction and western blotting. Additionally, RNA interference against IFN-ß or DDX60 was performed. Furthermore, cleavage of caspase 9 and poly (ADP-ribose) polymerase (PARP), markers of cells undergoing apoptosis, was examined using western blotting. We conducted an immunofluorescence study to examine endothelial DDX60 expression in biopsy specimens from patients with LN. RESULTS: We observed that endothelial expression of DDX60 was induced by poly IC but not by R848 or CpG, and RNA interference against IFN-ß inhibited poly IC-induced DDX60 expression. DDX60 knockdown induced cleavage of caspase 9 and PARP. Intense endothelial DDX60 expression was observed in biopsy specimens from patients with diffuse proliferative LN. CONCLUSION: Glomerular endothelial DDX60 expression may prevent apoptosis, which is involved in the pathogenesis of LN. Modulating the upregulation of the regional innate immune system via TLR3 signaling may be a promising treatment target for LN.
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ARN Helicasas DEAD-box , Nefritis Lúpica , Receptor Toll-Like 3 , Antivirales , Caspasa 9/metabolismo , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Células Endoteliales/metabolismo , Humanos , Interferón beta/farmacología , Poli I-C/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/metabolismo , Receptor Toll-Like 3/genética , Receptor Toll-Like 3/metabolismoRESUMEN
Inherited bone-marrow-failure syndromes (IBMFSs) include heterogeneous genetic disorders characterized by bone-marrow failure, congenital anomalies, and an increased risk of malignancy. Many lines of evidence have suggested that p53 activation might be central to the pathogenesis of IBMFSs, including Diamond-Blackfan anemia (DBA) and dyskeratosis congenita (DC). However, the exact role of p53 activation in each clinical feature remains unknown. Here, we report unique de novo TP53 germline variants found in two individuals with an IBMFS accompanied by hypogammaglobulinemia, growth retardation, and microcephaly mimicking DBA and DC. TP53 is a tumor-suppressor gene most frequently mutated in human cancers, and occasional germline variants occur in Li-Fraumeni cancer-predisposition syndrome. Most of these mutations affect the core DNA-binding domain, leading to compromised transcriptional activities. In contrast, the variants found in the two individuals studied here caused the same truncation of the protein, resulting in the loss of 32 residues from the C-terminal domain (CTD). Unexpectedly, the p53 mutant had augmented transcriptional activities, an observation not previously described in humans. When we expressed this mutant in zebrafish and human-induced pluripotent stem cells, we observed impaired erythrocyte production. These findings together with close similarities to published knock-in mouse models of TP53 lacking the CTD demonstrate that the CTD-truncation mutations of TP53 cause IBMFS, providing important insights into the previously postulated connection between p53 and IBMFSs.
Asunto(s)
Enfermedades de la Médula Ósea/genética , Médula Ósea/patología , Células Germinativas/patología , Mutación/genética , Proteína p53 Supresora de Tumor/genética , Adolescente , Adulto , Agammaglobulinemia/genética , Anemia de Diamond-Blackfan/genética , Animales , Preescolar , Eritrocitos/patología , Femenino , Trastornos del Crecimiento/genética , Humanos , Células Madre Pluripotentes Inducidas/patología , Lactante , Recién Nacido , Masculino , Ratones , Persona de Mediana Edad , Adulto Joven , Pez CebraRESUMEN
The variability in myelosuppression after chemotherapy for acute myeloid leukaemia (AML) can affect its prognosis; however, the underlying mechanism remains controversial. In the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study, we showed that prolonged neutropenia was associated with high overall survival (P = 0·011) and low frequency of relapse (P = 0·042) in patients without granulocyte-colony stimulating factor (G-CSF) who completed the indicated treatment protocol. Our data indicate that predisposition to prolonged neutropenia after chemotherapy is correlated with a better outcome of AML treatment. Our results promote the usage of individualised drug dosing strategies to improve the therapeutic outcome in AML patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Factor Estimulante de Colonias de Granulocitos/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/inmunología , Neutropenia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trastornos de Fallo de la Médula Ósea/inducido químicamente , Niño , Susceptibilidad a Enfermedades , Femenino , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Humanos , Japón/epidemiología , Leucemia Mieloide Aguda/mortalidad , Masculino , Neutropenia/epidemiología , Pronóstico , Análisis de SupervivenciaRESUMEN
BACKGROUND: The prognosis of children with acute myeloid leukemia (AML) has improved with the efficacy of hematopoietic cell transplantation (HCT) as a second-line therapy and improvements in supportive care following anthracycline- and cytarabine-based chemotherapy; however, the outcomes of children with relapsed AML still remain unsatisfactory. PROCEDURE: In order to identify prognostic factors and improve their prognosis, we analyzed 111 patients who relapsed after treatment with the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 protocol and who were registered in the retrospective JPLSG AML-05R study. RESULTS: The 5-year overall survival rate was 36.1%. The major determinant of survival was duration from the diagnosis to relapse. The mean duration in the nonsurviving group (10.1 ± 4.1 months) was shorter than that in the surviving group (16.3 ± 8.3 months) (P < .01). Moreover, achieving a second complete remission (CR2) prior to HCT was associated with a good prognosis (P < .01). Etoposide, cytarabine, and mitoxantrone (ECM)- or fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG)-based regimens were therefore recommended for reinduction therapy (P < .01). A genetic analysis also revealed the prognostic significance of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication as a poor prognostic marker (P = .04) and core binding factor-AML, t(8;21), and inv(16) as good prognostic markers (P < .01). CONCLUSIONS: Achieving a CR2 prior to HCT is important in order to improve the prognosis of relapsed pediatric AML. Recent molecular targeted therapies, such as FLT3 inhibitors, may contribute to overcome their prognoses. Larger prospective investigations are necessary to establish individualized treatment strategies for patients with relapsed childhood AML.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/mortalidad , Leucemia Mieloide Aguda/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Adolescente , Antraciclinas/administración & dosificación , Biomarcadores de Tumor/genética , Niño , Preescolar , Terapia Combinada , Citarabina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Lactante , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Masculino , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante Homólogo , Vidarabina/administración & dosificación , Vidarabina/análogos & derivadosRESUMEN
Although thiopurine is a crucial drug for treating acute lymphoblastic leukemia, individual variations in intolerance are observed due to gene polymorphisms. A 3-year-old boy with B-cell precursor acute lymphoblastic leukemia who was administered thiopurine developed mucositis, sepsis, and hemophagocytic lymphohistiocytosis due to prolonged hematologic toxicity, chronic disseminated candidiasis, and infective endocarditis that triggered multiple brain infarctions. The patient was found to harbor 3 gene polymorphisms associated with thiopurine intolerance including homozygous NUDT15 R139C, heterozygous ITPA C94A, and homozygous MTHFR C677T and heterozygous RFC1 G80A. Thus, the combined effect of intolerance via multiple gene polymorphisms should be considered in case of unexpected adverse reactions.
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Hipersensibilidad a las Drogas/patología , Homocigoto , Mercaptopurina/efectos adversos , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pirofosfatasas/genética , Antimetabolitos Antineoplásicos , Infarto Encefálico/inducido químicamente , Infarto Encefálico/genética , Infarto Encefálico/patología , Preescolar , Hipersensibilidad a las Drogas/etiología , Humanos , Infecciones/inducido químicamente , Infecciones/genética , Infecciones/patología , Linfohistiocitosis Hemofagocítica/inducido químicamente , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/patología , Masculino , Mucositis/inducido químicamente , Mucositis/genética , Mucositis/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Sepsis/inducido químicamente , Sepsis/genética , Sepsis/patologíaRESUMEN
Diamond-Blackfan anemia (DBA) is mainly caused by pathogenic variants in ribosomal proteins and 22 responsible genes have been identified to date. The most common causative gene of DBA is RPS19 [NM_001022.4]. Nearly 180 RPS19 variants have been reported, including three deep intronic variants outside the splicing consensus sequence (c.72-92A > G, c.356 + 18G > C, and c.411 + 6G > C). We also identified one case with a c.412-3C > G intronic variant. Without conducting transcript analysis, the pathogenicity of these variants is unknown. However, it is difficult to assess transcripts because of their fragility. In such cases, in vitro functional splicing assays can be used to assess pathogenicity. Here, we report functional splicing analysis results of four RPS19 deep intronic variants identified in our case and in previously reported cases. One splicing consensus variant (c.411 + 1G > A) was also examined as a positive control. Aberrant splicing with a 2-bp insertion between exons 5 and 6 was identified in the patient samples and minigene assay results also identified exon 6 skipping in our case. The exon 6 skipping transcript was confirmed by further evaluation using quantitative RT-PCR. Additionally, minigene assay analysis of three reported deep intronic variants revealed that none of them showed aberrant splicing and that these variants were not considered to be pathogenic. In conclusion, the minigene assay is a useful method for functional splicing analysis of inherited disease.
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Anemia de Diamond-Blackfan , Mutación , Empalme del ARN , Proteínas Ribosómicas , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/metabolismo , Humanos , Recién Nacido , Masculino , Proteínas Ribosómicas/biosíntesis , Proteínas Ribosómicas/genéticaRESUMEN
Myeloid leukemia associated with Down syndrome (ML-DS) is characterized by a predominance of acute megakaryoblastic leukemia, the presence of GATA1 mutations and a favorable outcome. Because DS children can also develop conventional acute myeloid leukemia with unfavorable outcome, detection of GATA1 mutations is important for diagnosis of ML-DS. However, myelofibrosis and the significant frequency of dry taps have hampered practical screening of GATA1 mutations using bone marrow (BM) samples. In response to those problems, 82 patients were enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-D11 study. GATA1 mutations were analyzed by Sanger sequencing (SS) using genomic DNA (gDNA) from BM and cDNA from peripheral blood (PB) followed by targeted next-generation sequencing (NGS) using pooled diagnostic samples. BM and PB samples were obtained from 71 (87%) and 82 (100%) patients, respectively. GATA1 mutations were detected in 46 (56%) and 58 (71%) patients by SS using BM gDNA and PB cDNA, respectively. Collectively, GATA1 mutations were identified in 73/82 (89%) patients by SS. Targeted NGS detected GATA1 mutations in 74/82 (90%) patients. Finally, combining the results of SS with those of targeted NGS, GATA1 mutations were identified in 80/82 (98%) patients. These results indicate that SS using BM gDNA and PB cDNA is a rapid and useful method for screening for GATA1 mutations in ML-DS patients. Thus, a combination of SS and targeted NGS is a sensitive and useful method to evaluate the actual incidence and clinical significance of GATA1 mutations in ML-DS patients.
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Síndrome de Down/complicaciones , Síndrome de Down/genética , Factor de Transcripción GATA1/genética , Predisposición Genética a la Enfermedad , Leucemia Megacarioblástica Aguda/complicaciones , Leucemia Megacarioblástica Aguda/genética , Mutación , Adolescente , Adulto , Alelos , Sustitución de Aminoácidos , Biopsia , Médula Ósea/patología , Niño , Análisis Mutacional de ADN , Síndrome de Down/diagnóstico , Femenino , Estudios de Asociación Genética , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Japón , Leucemia Megacarioblástica Aguda/diagnóstico , Masculino , Adulto JovenRESUMEN
Inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders characterized by bone marrow failure, congenital anomalies, and increased risk of malignant disease. Next generation sequencing methods have greatly facilitated the discovery of genetic etiology in IBMFS. Recently, de novo mutations activating TP53 were detected in patients with BMFS, mimicking Diamond-Blackfan anemia (DBA), using whole exome sequencing, and these patients were recognized as having a novel disorder. This discovery provides important insights into the previously postulated connection between p53 activation and IBMFS. Furthermore, a novel IBMFS, aldehyde degradation deficiency syndrome, was found in patients with aplastic anemia resembling Fanconi anemia (FA). This disorder is caused by combined inactivating mutations in ADH5 and ALDH2 coding formaldehyde-detoxifying enzymes. In this review, we highlight recent studies on DBA, FA, and their related diseases in Japan.
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Anemia Aplásica , Anemia de Diamond-Blackfan , Enfermedades de la Médula Ósea , Hemoglobinuria Paroxística , Aldehído Deshidrogenasa Mitocondrial , Anemia Aplásica/diagnóstico , Anemia Aplásica/genética , Anemia de Diamond-Blackfan/genética , Enfermedades de la Médula Ósea/genética , Trastornos de Fallo de la Médula Ósea , Síndromes Congénitos de Insuficiencia de la Médula Ósea , Hemoglobinuria Paroxística/diagnóstico , Hemoglobinuria Paroxística/genética , HumanosRESUMEN
Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for juvenile myelomonocytic leukemia (JMML), but few large studies of HSCT for JMML exist. Using data from the Japan Society for Hematopoietic Cell Transplantation registry, we analyzed the outcomes of 129 children with JMML who underwent HSCT between 2000 and 2011. The 5-year overall survival (OS) rate and cumulative incidence of relapse were 64% and 34%, respectively. A regimen of busulfan/fludarabine/melphalan was the most commonly used (59 patients) and provided the best outcomes; the 5-year OS rate reached 73%, and the cumulative incidences of relapse and transplantation-related mortality were 26% and 9%, respectively. In contrast, the use of the irradiation-based myeloablative regimen was the most significant risk factor for OS (hazard ratio [HR], 2.92; P = .004) in the multivariate model. In addition, chronic graft-versus-host disease (GVHD) was strongly associated with lower relapse (HR, 0.37; P = .029) and favorable survival (HR, 0.22; P = .006). The current study has shown that a significant proportion of children with JMML can be cured with HSCT, especially those receiving the busulfan/fludarabine/melphalan regimen. Based on the lower relapse and better survival observed in patients with chronic GVHD, additional treatment strategies that focus on enhancing graft-versus-leukemia effects may further improve survival.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mielomonocítica Juvenil , Busulfano/uso terapéutico , Niño , Enfermedad Injerto contra Huésped/etiología , Humanos , Japón , Leucemia Mielomonocítica Juvenil/terapia , Estudios Retrospectivos , Acondicionamiento Pretrasplante , VidarabinaRESUMEN
BACKGROUND: Transient abnormal myelopoiesis (TAM) is a unique myeloproliferative disorder that occurs in neonates with constitutional trisomy 21/Down syndrome (DS). Although TAM also develops in neonates without constitutional trisomy 21, the clinical, cytogenetic, and molecular characteristics of those patients are not fully understood. PROCEDURE: We retrospectively evaluated the clinical and cytogenetic findings and GATA1 mutation status of 17 neonates with TAM and nonconstitutional trisomy 21 tested for GATA1 mutations at our institute, and compared the findings with those of 64 neonates with TAM and constitutional trisomy 21/DS. RESULTS: DS clinical features were observed in five of the 17 (29%) patients. In all patients, both trisomy 21 and GATA1 mutations were detected in diagnostic samples. Over a median follow-up of 33 (range, 0-139) months, early death (< 6 months of age) occurred in four patients (24%). Overall and event-free survivals were not significantly different between the patients with TAM and nonconstitutional trisomy 21 and those with TAM and constitutional trisomy 21/DS (five-year overall survival: 76% ± 10% vs 53% ± 13%, P = 0.40; five-year event-free survival: 55% ± 13% vs 48% ± 12%, P = 0.90). The five-year cumulative incidence of progression to myeloid leukemia of DS was also similar between the groups (21% vs 24%, P = 0.80). CONCLUSIONS: Patients with TAM and nonconstitutional trisomy 21 exhibited similar biology and outcomes to those with TAM and constitutional trisomy 21/DS. The possibility of TAM should be considered even in phenotypically normal neonates with TAM symptoms, for appropriate management.
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Cromosomas Humanos Par 21/genética , Síndrome de Down , Factor de Transcripción GATA1/genética , Mutación , Mielopoyesis/genética , Supervivencia sin Enfermedad , Síndrome de Down/genética , Síndrome de Down/mortalidad , Síndrome de Down/patología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Tasa de SupervivenciaRESUMEN
We previously reported that risk-stratified therapy and intensive postremission chemotherapy (PRC) contributed to the improved survival of childhood acute myeloid leukemia (AML) in the AML99 study, which led us to consider a reduction in the number of PRC courses with more restrictive indications for stem cell transplantation (SCT) in the successor AML-05 study. We here report the outcome of AML patients without core-binding factor mutation (non-CBF AML) in the AML-05 study. Two-hundred eighty-nine children (age < 18 years old) with non-CBF AML were eligible. Patients with unfavorable cytogenetics and/or poor bone marrow response to the first induction course were candidates for SCT in the AML-05 study. After two courses of induction, a further three courses of PRC were given in AML-05, while four courses were given in the AML99 study. The 3-year event-free survival (EFS) rate in the AML-05 study (46.7%, 95% CI: 40.6-52.6%) was comparable to that of non-CBF AML in the AML99 study (51.5%, 95% CI: 42.7-59.6%) (P = .16). However, the 3-year overall survival (OS) rate in the AML-05 study (62.9%, 95% CI: 56.3-68.8%) was slightly lower than that in the AML99 study (71.6%, 95% CI: 63.2-78.5%) (P = .060), mainly due to decreased remission induction rate and increased nonrelapsed mortality. In conclusion, reductions in the number of PRC courses from four to three, together with repetitive cycles of high-dose cytarabine, were acceptable for non-CBF childhood AML.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factores de Unión al Sitio Principal/genética , Leucemia Mieloide Aguda/terapia , Trasplante de Células Madre/mortalidad , Adolescente , Antraciclinas/administración & dosificación , Niño , Preescolar , Terapia Combinada , Citarabina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Quimioterapia de Inducción , Lactante , Japón , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Mutación , Pronóstico , Inducción de Remisión , Estudios Retrospectivos , Sociedades Médicas , Tasa de SupervivenciaRESUMEN
A 3-year-old boy was clinically diagnosed with Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis. We identified EBV-infected CD8-positive T-lymphocytes by cytologic double staining of the peripheral blood for EBV-encoded small RNA and cell surface markers. The patient was subsequently administered immunosuppressive therapy with a reduced dose of etoposide because of previous organ damage. EBV clearance was confirmed by serial quantification of cell-fractionated EBV-DNA, whereas EBV-DNA persisted in the plasma for 18 weeks. Immunochemotherapy with low-dose etoposide combined with serial viral load monitoring is a potential therapeutic option for severe EBV-hemophagocytic lymphohistiocytosis cases with organ damage.