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1.
Rinsho Ketsueki ; 61(1): 39-43, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-32023601

RESUMEN

There are few reports of a patient presenting with combined follicular lymphoma (FL) and classical Hodgkin lymphoma (cHL). A 37-year-old Japanese man was diagnosed with FL with generalized lymphadenopathy and treated with R-CHOP. Four months later, he presented with fever, elevated lactic acid dehydrogenase (LDH), and pancytopenia. Consequently, he was diagnosed with cHL in the bone marrow. Identical clonality of FL and cHL tumor cells suggested identical immunoglobulin heavy chain gene rearrangements. He was treated with salvage chemotherapy and high-dose chemotherapy with autologous hematopoietic stem cell transformation (HDT-ASCT), which has led to complete remission and no recurrence for more than two years after transplantation. Our case suggests that HDT-ASCT may be an effective treatment for this rare clinical condition.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin , Linfoma Folicular , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Masculino , Recurrencia Local de Neoplasia , Rituximab , Trasplante Autólogo
2.
Ann Hematol ; 98(1): 83-91, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30251205

RESUMEN

We analyzed the clinical significance and genetic features of ASXL2 and ZBTB7A mutations, and the alternatively spliced isoform of the RUNX1-RUNX1T1 transcript, which is also called AML1-ETO9a (AE9a), in Japanese CBF-AML patients enrolled in the JALSG AML201 study. ASXL2 and ZBTB7A genes were sequenced using bone marrow samples of 41 AML patients with t(8;21) and 14 with inv(16). The relative expression levels of AE9a were quantified using the real-time PCR assay in 23 AML patients with t(8;21). We identified ASXL2 (34.1%) and ZBTB7A (9.8%) mutations in only AML patients with t(8;21). ASXL2-mutated patients had a significantly higher WBC count at diagnosis (P = 0.04) and a lower frequency of sex chromosome loss than wild-type patients (33 vs. 76%, respectively, P = 0.01). KIT mutations were the most frequently accompanied with both ASXL2 (36%) and ZBTB7A (75%) mutations. Neither ASXL2 nor ZBTB7A mutations had an impact on overall or event-free survival. Patients harboring cohesin complex gene mutations expressed significantly higher levels of AE9a than unmutated patients (P = 0.03). In conclusion, ASXL2 and ZBTB7A mutations were frequently identified in Japanese AML patients with t(8;21), but not in those with inv(16). Further analysis is required to clarify the detailed biological mechanism of AE9a regulation of the cohesin complex.


Asunto(s)
Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 8/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Proteínas de Unión al ADN , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda , Proteínas de Fusión Oncogénica , Proteína 1 Compañera de Translocación de RUNX1 , Proteínas Represoras , Factores de Transcripción , Translocación Genética , Adolescente , Adulto , Anciano , Niño , Subunidad alfa 2 del Factor de Unión al Sitio Principal/biosíntesis , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/biosíntesis , Proteínas de Fusión Oncogénica/genética , Proteína 1 Compañera de Translocación de RUNX1/biosíntesis , Proteína 1 Compañera de Translocación de RUNX1/genética , Proteínas Represoras/biosíntesis , Proteínas Represoras/genética , Tasa de Supervivencia , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética
3.
Sci Rep ; 14(1): 15906, 2024 07 10.
Artículo en Inglés | MEDLINE | ID: mdl-38987297

RESUMEN

Most of essential thrombocythemia (ET) patients have the clone harboring a mutation in one of the JAK2, CALR, or MPL gene, and these clones generally acquire additional mutations at transformation to acute myeloid leukemia (AML). However, the proliferation of triple-negative clones has sometimes been observed at AML transformation. To clarify the clonal evolution of ET to AML, we analyzed paired samples at ET and AML transformation in eight patients. We identified that JAK2-unmutated AML clones proliferated at AML transformation in three patients in whom the JAK2-mutated clone was dominant at ET. In two patients, TET2-mutated, but not JAK2-mutated, clones might be common initiating clones for ET and transformed AML. In a patient with JAK2-mutated ET, SMARCC2, UBR4, and ZNF143, but not JAK2, -mutated clones proliferated at AML transformation. Precise analysis using single-cell sorted CD34+/CD38- fractions suggested that ET clone with JAK2-mutated and AML clone with TP53 mutation was derived from the common clone with these mutations. Although further study is required to clarify the biological significance of SMARCC2, UBR4, and ZNF143 mutations during disease progression of ET and AML transformation, the present results demonstrate the possibility of a common initial clone involved in both ET and transformed AML.


Asunto(s)
Janus Quinasa 2 , Leucemia Mieloide Aguda , Mutación , Trombocitemia Esencial , Humanos , Trombocitemia Esencial/genética , Trombocitemia Esencial/complicaciones , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Femenino , Janus Quinasa 2/genética , Persona de Mediana Edad , Anciano , Adulto , Anciano de 80 o más Años , Transformación Celular Neoplásica/genética , Dioxigenasas , Evolución Clonal/genética , Proteínas de Unión al ADN
4.
Nat Commun ; 13(1): 1624, 2022 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-35338146

RESUMEN

Patient-derived xenografts (PDX) are widely used as human cancer models. Previous studies demonstrated clonal discordance between PDX and primary cells. However, in acute myeloid leukemia (AML)-PDX models, the significance of the clonal dynamics occurring in PDX remains unclear. By evaluating changes in the variant allele frequencies (VAF) of somatic mutations in serial samples of paired primary AML and their PDX bone marrow cells, we identify the skewing engraftment of relapsed or refractory (R/R) AML clones in 57% of PDX models generated from multiclonal AML cells at diagnosis, even if R/R clones are minor at <5% of VAF in patients. The event-free survival rate of patients whose AML cells successfully engraft in PDX models is consistently lower than that of patients with engraftment failure. We herein demonstrate that primary AML cells including potentially chemotherapy-resistant clones dominantly engraft in AML-PDX models and they enrich pre-existing treatment-resistant subclones.


Asunto(s)
Leucemia Mieloide Aguda , Animales , Células de la Médula Ósea , Células Clonales , Modelos Animales de Enfermedad , Humanos , Leucemia Mieloide Aguda/genética , Ratones
5.
Intern Med ; 60(8): 1271-1277, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33162482

RESUMEN

Though adult-onset primary autoimmune pancytopenia (AIP) rarely follows a self-limited course, a standard treatment strategy has not yet been established. We herein report two cases, each involving primary autoimmune neutropenia complicated with autoimmune thrombocytopenia or Evans syndrome. They were refractory to granulocyte-colony stimulating factor, but all lineages of cytopenia promptly recovered with prednisolone (PSL). In case 1, PSL was tapered and discontinued six months after its initiation without AIP relapse. In case 2, PSL has been tapered for five months without relapse. To establish an optimal treatment strategy for AIP, it is necessary to accumulate more cases.


Asunto(s)
Anemia Hemolítica Autoinmune , Enfermedades Autoinmunes , Neutropenia , Trombocitopenia , Adulto , Anemia Hemolítica Autoinmune/complicaciones , Anemia Hemolítica Autoinmune/diagnóstico , Anemia Hemolítica Autoinmune/tratamiento farmacológico , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Neutropenia/tratamiento farmacológico , Prednisolona/uso terapéutico , Trombocitopenia/complicaciones , Trombocitopenia/tratamiento farmacológico
6.
Leuk Res ; 65: 34-41, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29306105

RESUMEN

The myeloperoxidase (MPO)-positivity of blasts in bone marrow smears is an important marker for not only the diagnosis, but also the prognosis of acute myeloid leukemia (AML). To investigate the relationship between genetic alterations and MPO-positivity, we performed targeted sequencing for 51 genes and 10 chimeric gene transcripts in 164 newly diagnosed de novo AML patients; 107 and 57 patients were classified as AML with >50% MPO-positive blasts (MPO-high group) and ≤50% MPO-positive blasts, (MPO-low group), respectively. The univariate analysis revealed that RUNX1-RUNX1T1 (P < 0.001), the KIT mutation (P < 0.001), and CEBPA double mutation (P = 0.001) were more likely to be found in the MPO-high group, while the DNMT3A mutation (P = 0.001), FLT3 tyrosine kinase domain mutation (P = 0.004), and TP53 mutation (P = 0.020) were more likely to be present in the MPO-low group. Mutations in genes related to DNA hypermethylation signatures (IDH1, IDH2, TET2, and WT1 genes) were more frequent in the MPO-high group (P = 0.001) when patients with fusion genes of core-binding factors were excluded from the analysis. Our results suggest that MPO-positivity of blasts was related with the distinct gene mutation patterns among de novo AML patients.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Genes Relacionados con las Neoplasias , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Mutación , Peroxidasa/metabolismo , Adolescente , Adulto , Metilación de ADN/genética , Regulación Leucémica de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/clasificación , Leucemia Mieloide Aguda/enzimología , Persona de Mediana Edad , Pronóstico , ARN Mensajero/genética , Adulto Joven
7.
Leuk Res ; 66: 20-27, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29360622

RESUMEN

Many genetic alterations that are associated with the prognosis of acute myeloid leukemia (AML) have been identified, and several risk stratification systems based on the genetic status have been recommended. The European LeukemiaNet (ELN) first proposed the risk stratification system for AML in 2010 (ELN-2010), and recently published the revised system (ELN-2017). We validated the long-term prognosis and clinical characteristics of each ELN-2017 risk category in Japanese adult AML patients who were treated in the Japan Adult Leukemia Study Group (JALSG) AML-201 study. We demonstrated that the 3-risk category system of the ELN-2017 successfully discriminated the overall survival and complete remission rates in our cohort in comparison with the 4-risk category of the ELN-2010. However, there were still genetic categories in which stratification of patients into favorable or intermediate risk categories was controversial; the low allelic ratio of FLT3-ITD was not necessarily associated with a better prognosis in patients with FLT3-ITD, and cytogenetic abnormalities may affect the prognosis in patients with favorable genetic lesions such as NPM1 and CEBPA mutations. As many molecular targeting agents, such as FLT3 inhibitors, have been developed, we must continue to modify the genetic risk stratification system to match the progression of therapeutic strategies.


Asunto(s)
Proteínas Potenciadoras de Unión a CCAAT , Leucemia Mieloide Aguda , Proteínas Nucleares , Inhibidores de Proteínas Quinasas/administración & dosificación , Tirosina Quinasa 3 Similar a fms , Adolescente , Adulto , Pueblo Asiatico , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Japón , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleofosmina , Medición de Riesgo , Tasa de Supervivencia , Factores de Tiempo , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo
8.
Int J Hematol ; 107(2): 201-210, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29027108

RESUMEN

Clinical outcomes and the genetic background of acute myeloid leukemia (AML) in adolescent and young adults (AYAs) are known to differ in younger children and older adults. To clarify the impact of genetic mutations on clinical outcomes of AYAs with AML, we analyzed data from the JPLSG AML-05 and JALSG AML201 studies. AYAs aged 15-39 years (n = 103) were included. FLT3-ITD, KIT, CEBPA, NRAS, KRAS, WT1, MLL-PTD, and NPM1 mutations were analyzed. Overall survival (OS) of the AYAs was 61% and event-free survival was 38% at 3 years. FLT3-ITD (HR 2.10; 95% CI 1.07-4.12; p = 0.031) and NPM1 (HR 0.24; 95% CI 0.06-1.00; p = 0.050) mutations were associated with risk of overall mortality in multivariate analysis. OS was significantly different according to FLT3-ITD and NPM1 mutation status (p = 0.03). Survival was 100% with NPM1 mutations in the absence of FLT3-ITD and 35% (95% CI 14-57%) with FLT3-ITD in the absence of NPM1 mutations. The OS of AYAs, children (n = 413) and older adults (n = 124) of the AML-05 and AML201 participants were significantly different (p < 0.0001). This is the first report to combine clinical and genetic data of AYA AML from the major Japanese pediatric and adult study groups.


Asunto(s)
Leucemia Mieloide Aguda/genética , Mutación , Proteínas Nucleares/genética , Tirosina Quinasa 3 Similar a fms/genética , Adolescente , Humanos , Leucemia Mieloide Aguda/mortalidad , Análisis Multivariante , Nucleofosmina , Pronóstico , Tasa de Supervivencia , Adulto Joven
9.
Leuk Res Rep ; 2(1): 21-5, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24371770

RESUMEN

We identified two novel GATA2 mutations in acute myeloid leukemia (AML). One mutation (p.R308P-GATA2) was a R308P substitution within the zinc finger (ZF)-1 domain, and the other (p.A350_N351ins8-GATA2) was an eight-amino-acid insertion between A350 and N351 residues within the ZF-2 domain. p.R308P-GATA2 did not affect DNA-binding and transcriptional activities, while p.A350_N351ins8-GATA2 reduced them, and impaired G-CSF-induced granulocytic differentiation of 32D cells. Although p.A350_N351ins8-GATA2 did not show a dominant-negative effect over wild-type (Wt)-GATA2 by the reporter assay, it might be involved in the pathophysiology of AML by impairing myeloid differentiation because of little Wt-GATA2 expression in primary AML cells harboring the p.A350_N351ins8 mutation.

10.
Int J Hematol ; 97(1): 98-102, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23243003

RESUMEN

Mature T cell lymphoma has been noted for poor prognosis when compared with B cell lymphoma, even in the pre-rituximab era. To confirm this difference, a retrospective cohort study was conducted. One hundred-and nineteen patients with mature T cell lymphoma and 568 patients with diffuse large B cell lymphoma (DLBCL) who did not receive rituximab as first induction were studied. Overall survival (OS) was worse for patients with international prognostic index (IPI) scores indicating low-risk mature T cell lymphoma than for those with DLBCL (3-year OS 87 % vs. 58 %, P = 0.001), but not in other risk groups. Prognosis of mature T cell lymphoma was significantly poorer in the IPI low-risk group, as compared with DLBCL.


Asunto(s)
Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células T/mortalidad , Linfoma de Células T/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Adulto Joven
11.
Leuk Res ; 35(10): 1384-9, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21565405

RESUMEN

Barasertib (AZD1152) is a highly potent and selective Aurora B kinase inhibitor. The safety, efficacy and pharmacokinetic (PK) profile of barasertib were investigated in Japanese patients with advanced acute myeloid leukemia. Barasertib (50-1200mg) was administered as a continuous 7-day intravenous infusion every 21 days. No dose-limiting toxicities were reported and barasertib 1200mg was chosen for further evaluation in Japanese patients. Neutropenia and febrile neutropenia were the most commonly reported adverse events. The PK profile was similar to Western patients. A promising overall hematologic response rate of 19% was achieved, which warrants further investigation in these patients.


Asunto(s)
Antineoplásicos/farmacocinética , Inhibidores Enzimáticos/farmacocinética , Leucemia Mieloide Aguda , Organofosfatos/farmacocinética , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Quinazolinas/farmacocinética , Adulto , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Pueblo Asiatico , Aurora Quinasa B , Aurora Quinasas , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Neutropenia/patología , Organofosfatos/administración & dosificación , Organofosfatos/efectos adversos , Proteínas Serina-Treonina Quinasas/metabolismo , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Resultado del Tratamiento
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