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1.
Biochem Biophys Res Commun ; 710: 149541, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38608490

RESUMEN

For acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) is well established. However, the narrow application and tolerance development of ATRA remain to be improved. In this study, we investigated the effects of combinations of glycosylation inhibitors with ATRA to achieve better efficiency than ATRA alone. We found that the combination of fucosylation inhibitor 6-alkynylfucose (6AF) and ATRA had an additional effect on cell differentiation, as revealed by expression changes in two differentiation markers, CD11b and CD11c, and significant morphological changes in NB4 APL and HL-60 acute myeloid leukemia (AML) cells. In AAL lectin blot analyses, ATRA or 6AF alone could decrease fucosylation, while their combination decreased fucosylation more efficiently. To clarify the molecular mechanism for the 6AF effect on ATRA-induced differentiation, we performed microarray analyses using NB4 cells. In a pathway analysis using DAVID software, we found that the C-type lectin receptor (CLR) signaling pathway was enriched with high significance. In real-time PCR analyses using NB4 and HL-60 cells, FcεRIγ, CLEC6A, CLEC7A, CASP1, IL-1ß, and EGR3, as components of the CLR pathway, as well as CD45 and AKT3 were upregulated by 6AF in ATRA-induced differentiation. Taken together, the present findings suggest that the CLR signaling pathway is involved in the 6AF effect on ATRA-induced differentiation.


Asunto(s)
Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/metabolismo , Glicosilación , Tretinoina/farmacología , Tretinoina/metabolismo , Diferenciación Celular , Células HL-60 , Línea Celular Tumoral
2.
Tohoku J Exp Med ; 259(2): 113-119, 2023 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-36450481

RESUMEN

Lenalidomide (LEN), one of the key drugs in the treatment of myelodysplastic syndromes (MDS) with 5q deletion, as well as multiple myeloma (MM), has various immunomodulatory effects and has been associated with autoimmune diseases, including immune thrombocytopenic purpura (ITP). A 78-year-old man presented with pancytopenia and was diagnosed with MDS with 5q deletion and other chromosomal abnormalities. Two cycles of LEN therapy (one cycle: 10 mg/day for 21 days) resulted in a transient improvement in anemia, followed by MDS progression with severe thrombocytopenia (4 × 109/L) refractory to platelet transfusions. As other non-immune and alloimmune causes of transfusion-refractory thrombocytopenia were excluded, and the level of platelet-associated immunoglobulin G was extremely high compared with the level before treatment with LEN, the diagnosis of ITP was highly suspected. Despite treatment with prednisolone (PSL), eltrombopag, and repeated platelet transfusions, his platelet count did not increase, and he died of a gastrointestinal hemorrhage. Several cases of ITP induced by LEN used to treat MM had been reported, but the platelet count recovered after administration of PSL in these previous cases. However, we should be mindful of using LEN for patients with MDS because its treatment may become extremely difficult if ITP develops.


Asunto(s)
Mieloma Múltiple , Síndromes Mielodisplásicos , Púrpura Trombocitopénica Idiopática , Trombocitopenia , Masculino , Humanos , Anciano , Lenalidomida/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/tratamiento farmacológico , Cromosomas
3.
J Infect Chemother ; 26(2): 292-295, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31570321

RESUMEN

Fusariosis is a critical infectious complication that can develop in immunocompromised hosts, mainly under conditions of prolonged neutropenia, and is often disseminated and associated with a high mortality rate. Disseminated fusariosis developing during the course of hematopoietic stem cell transplantation (HSCT) is a critical condition, and there have been few reports of successful treatment of cases complicated with fusariosis before HSCT. Here, we present a case of acute myeloid leukemia (AML) with the development of fungal endophthalmitis during chemotherapy. Vitrectomy was performed and Fusarium solani infection was confirmed by vitreal culture. The infection was also disseminated to the lung, triceps, and spleen. The splenic lesions disappeared with the administration of antifungal agents, and residual lesions in the lung and triceps were surgically resected. After two courses of consolidation chemotherapy, the patient received cord blood transplantation (CBT) twice because of graft failure in the first transplantation. Antifungal agents were administered continuously during chemotherapy and transplantation. Although Fusarium sinusitis developed after neutrophil engraftment, it was well controlled by surgical resection. Thereafter, the patient has been well without recurrence of fusariosis for more than 2 years since transplantation. A combination of continuous administration of antifungal agents and vigorous surgical intervention may be important for management of disseminated fusariosis in the setting of HSCT.


Asunto(s)
Antifúngicos/uso terapéutico , Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Fusariosis/complicaciones , Fusariosis/tratamiento farmacológico , Leucemia Mieloide Aguda/terapia , Adolescente , Antibacterianos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Supervivientes de Cáncer , Endoftalmitis/complicaciones , Endoftalmitis/tratamiento farmacológico , Fusarium/aislamiento & purificación , Humanos , Huésped Inmunocomprometido , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Neutropenia/complicaciones , Neutropenia/tratamiento farmacológico , Resultado del Tratamiento , Vitrectomía/métodos , Voriconazol/uso terapéutico
4.
Ann Hematol ; 98(1): 131-142, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29974231

RESUMEN

Peripheral T cell lymphomas are an aggressive group of non-Hodgkin lymphomas with poor outcomes for most subtypes and no accepted standard of care for relapsed patients. This study evaluated the efficacy and safety of forodesine, a novel purine nucleoside phosphorylase inhibitor, in patients with relapsed peripheral T cell lymphomas. Patients with histologically confirmed disease, progression after ≥ 1 prior treatment, and an objective response to last treatment received oral forodesine 300 mg twice-daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. Forty-eight patients (median age, 69.5 years; median of 2 prior treatments) received forodesine. In phase 1 (n = 3 evaluable), no dose-limiting toxicity was observed during the first 28 days of forodesine treatment. In phase 2 (n = 41 evaluable), the ORR for the primary and final analyses was 22% (90% CI 12-35%) and 25% (90% CI 14-38%), respectively, including four complete responses (10%). Median PFS and OS were 1.9 and 15.6 months, respectively. The most common grade 3/4 adverse events were lymphopenia (96%), leukopenia (42%), and neutropenia (35%). Dose reduction and discontinuation due to adverse events were uncommon. Secondary B cell lymphoma developed in five patients, of whom four were positive for Epstein-Barr virus. In conclusion, forodesine has single-agent activity within the range of approved therapies in relapsed peripheral T cell lymphomas, with a manageable safety profile, and may represent a viable treatment option for this difficult-to-treat population.


Asunto(s)
Linfoma de Células T Periférico/tratamiento farmacológico , Nucleósidos de Purina/administración & dosificación , Nucleósidos de Purina/farmacocinética , Pirimidinonas/administración & dosificación , Pirimidinonas/farmacocinética , Administración Oral , Adulto , Anciano , Femenino , Humanos , Linfoma de Células T Periférico/sangre , Masculino , Persona de Mediana Edad , Nucleósidos de Purina/efectos adversos , Pirimidinonas/efectos adversos , Recurrencia
5.
Blood ; 128(4): 508-18, 2016 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-27259979

RESUMEN

Dendritic cells (DCs) are critical immune response regulators; however, the mechanism of DC differentiation is not fully understood. Heterozygous germ line GATA2 mutations induce GATA2-deficiency syndrome, characterized by monocytopenia, a predisposition to myelodysplasia/acute myeloid leukemia, and a profoundly reduced DC population, which is associated with increased susceptibility to viral infections, impaired phagocytosis, and decreased cytokine production. To define the role of GATA2 in DC differentiation and function, we studied Gata2 conditional knockout and haploinsufficient mice. Gata2 conditional deficiency significantly reduced the DC count, whereas Gata2 haploinsufficiency did not affect this population. GATA2 was required for the in vitro generation of DCs from Lin(-)Sca-1(+)Kit(+) cells, common myeloid-restricted progenitors, and common dendritic cell precursors, but not common lymphoid-restricted progenitors or granulocyte-macrophage progenitors, suggesting that GATA2 functions in the myeloid pathway of DC differentiation. Moreover, expression profiling demonstrated reduced expression of myeloid-related genes, including mafb, and increased expression of T-lymphocyte-related genes, including Gata3 and Tcf7, in Gata2-deficient DC progenitors. In addition, GATA2 was found to bind an enhancer element 190-kb downstream region of Gata3, and a reporter assay exhibited significantly reduced luciferase activity after adding this enhancer region to the Gata3 promoter, which was recovered by GATA sequence deletion within Gata3 +190. These results suggest that GATA2 plays an important role in cell-fate specification toward the myeloid vs T-lymphocyte lineage by regulating lineage-specific transcription factors in DC progenitors, thereby contributing to DC differentiation.


Asunto(s)
Diferenciación Celular/inmunología , Células Dendríticas/inmunología , Factor de Transcripción GATA2/inmunología , Animales , Diferenciación Celular/genética , Células Dendríticas/citología , Factor de Transcripción GATA2/genética , Factor de Transcripción GATA3/genética , Factor de Transcripción GATA3/inmunología , Factor Nuclear 1-alfa del Hepatocito/genética , Factor Nuclear 1-alfa del Hepatocito/inmunología , Ratones , Ratones Noqueados , Células Mieloides/citología , Células Mieloides/inmunología , Linfocitos T/citología , Linfocitos T/inmunología
6.
Stem Cells ; 35(3): 739-753, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27641212

RESUMEN

Mesenchymal stromal cells (MSCs) are multipotent progenitor cells and there is much interest in how MSCs contribute to the regulation of the tumor microenvironment. Whether MSCs exert a supportive or suppressive effect on tumor progression is still controversial, but is likely dependent on a variety of factors that are tumor-type dependent. Multiple myeloma (MM) is characterized by growth of malignant plasma cells in the bone marrow. It has been shown that the progression of MM is governed by MSCs, which act as a stroma of the myeloma cells. Although stroma is created via mutual communication between myeloma cells and MSCs, the mechanism is poorly understood. Here we explored the role of lysophosphatidic acid (LPA) signaling in cellular events where MSCs were converted into either MM-supportive or MM-suppressive stroma. We found that myeloma cells stimulate MSCs to produce autotaxin, an indispensable enzyme for the biosynthesis of LPA, and LPA receptor 1 (LPA1) and 3 (LPA3) transduce opposite signals to MSCs to determine the fate of MSCs. LPA3-silenced MSCs (siLPA3-MSCs) exhibited cellular senescence-related phenotypes in vitro, and significantly promoted progression of MM and tumor-related angiogenesis in vivo. In contrast, siLPA1-MSCs showed resistance to cellular senescence in vitro, and efficiently delayed progression of MM and tumor-related angiogenesis in vivo. Consistently, anti-MM effects obtained by LPA1-silencing in MSCs were completely reproduced by systemic administration of Ki6425, an LPA1 antagonist. Collectively, our results indicate that LPA signaling determines the fate of MSCs and has potential as a therapeutic target in MM. Stem Cells 2017;35:739-753.


Asunto(s)
Senescencia Celular , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Mieloma Múltiple/irrigación sanguínea , Mieloma Múltiple/patología , Neovascularización Patológica/metabolismo , Receptores del Ácido Lisofosfatídico/metabolismo , Transducción de Señal , Animales , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Carcinogénesis/patología , Línea Celular Tumoral , Proliferación Celular , Transdiferenciación Celular , Progresión de la Enfermedad , Femenino , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Hidrolasas Diéster Fosfóricas/metabolismo , ARN Interferente Pequeño/metabolismo , Receptores del Ácido Lisofosfatídico/antagonistas & inhibidores , Regulación hacia Arriba , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Tohoku J Exp Med ; 244(1): 41-52, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29343653

RESUMEN

Hematopoietic stem cells can self-renew and differentiate into all blood cell types. The transcription factor GATA-2 is expressed in hematopoietic stem and progenitor cells and is essential for cell proliferation and differentiation. Heterozygous germline GATA2 mutations induce GATA-2 deficiency syndrome, characterized by monocytopenia, a predisposition to myelodysplasia and acute myeloid leukemia, and a profoundly reduced dendritic cell (DC) population, which is associated with increased susceptibility to viral infections. Because patients with GATA-2 deficiency syndrome could retain a wild-type copy of GATA-2, boosting residual wild-type GATA-2 activity may represent a novel therapeutic strategy for the disease. Here, we sought to establish a screening system to identify GATA-2 activators using human U937 monocytic cells as a potential model of the DC progenitor. Enforced GATA-2 expression in U937 cells induces CD205 expression, a marker of DC differentiation, indicating U937 cells as a surrogate of human primary DC progenitors. Transient luciferase reporter assays in U937 cells reveals a high promoter activity of the -0.5 kb GATA-2 hematopoietic-specific promoter (1S promoter) fused with two tandemly connected GATA-2 +9.9 kb intronic enhancers. We thus established U937-derived cell lines stably expressing tandem +9.9 kb/-0.5 kb 1S-luciferase. Importantly, forced GATA-1 expression, a repressor for GATA-2 expression, in the stable clones caused significant decreases in the luciferase activities. In conclusion, our system represents a potential tool for identifying novel regulators of GATA-2, thereby contributing to the development of novel therapeutic approaches.


Asunto(s)
Factor de Transcripción GATA2/genética , Regulación de la Expresión Génica , Pruebas Genéticas , Transcripción Genética , Emparejamiento Base/genética , Biomarcadores/metabolismo , Línea Celular Tumoral , Células Clonales , Células Dendríticas/metabolismo , Humanos , Sueros Inmunes/metabolismo , Luciferasas/metabolismo , Regiones Promotoras Genéticas/genética
9.
Biochem Biophys Res Commun ; 485(2): 380-387, 2017 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-28216155

RESUMEN

The transcription factor GATA-1-interacting protein Friend of GATA-1 (FOG1) is essential for proper transcriptional activation and repression of GATA-1 target genes; yet, the mechanisms by which FOG1 exerts its activating and repressing functions remain unknown. Forced FOG1 expression in human K562 erythroleukemia cells induced the expression of erythroid genes (SLC4A1, globins) but repressed that of GATA-2 and PU.1. A quantitative chromatin immunoprecipitation (ChIP) analysis demonstrated increased GATA-1 chromatin occupancy at both FOG1-activated as well as FOG1-repressed gene loci. However, while TAL1 chromatin occupancy was significantly increased at FOG1-activated gene loci, it was significantly decreased at FOG1-repressed gene loci. When FOG1 was overexpressed in TAL1-knocked down K562 cells, FOG1-mediated activation of HBA, HBG, and SLC4A1 was significantly compromised by TAL1 knockdown, suggesting that FOG1 may require TAL1 to activate GATA-1 target genes. Promoter analysis and quantitative ChIP analysis demonstrated that FOG1-mediated transcriptional repression of PU.1 would be mediated through a GATA-binding element located at its promoter, accompanied by significantly decreased H3 acetylation at lysine 4 and 9 (K4 and K9) as well as H3K4 trimethylation. Our results provide important mechanistic insight into the role of FOG1 in the regulation of GATA-1-regulated genes and suggest that FOG1 has an important role in inducing cells to differentiate toward the erythroid lineage rather than the myelo-lymphoid one by repressing the expression of PU.1.


Asunto(s)
Proteína 1 de Intercambio de Anión de Eritrocito/genética , Regulación Leucémica de la Expresión Génica , Proteínas Nucleares/genética , Proteínas Proto-Oncogénicas/genética , Transactivadores/genética , Factores de Transcripción/genética , Acetilación , Proteína 1 de Intercambio de Anión de Eritrocito/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Western Blotting , Línea Celular , Cromatina/genética , Cromatina/metabolismo , Factor de Transcripción GATA1/genética , Factor de Transcripción GATA1/metabolismo , Histonas/metabolismo , Humanos , Células K562 , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/metabolismo , Leucemia Eritroblástica Aguda/patología , Lisina/metabolismo , Proteínas Nucleares/metabolismo , Regiones Promotoras Genéticas/genética , Unión Proteica , Proteínas Proto-Oncogénicas/metabolismo , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína 1 de la Leucemia Linfocítica T Aguda , Transactivadores/metabolismo , Factores de Transcripción/metabolismo
10.
J Biol Chem ; 289(12): 8121-34, 2014 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-24492606

RESUMEN

EZH2, a core component of polycomb repressive complex 2 (PRC2), plays a role in transcriptional repression through histone H3 Lys-27 trimethylation and is involved in various biological processes, including hematopoiesis. It is well known that 3-deazaneplanocin A (DZNep), an inhibitor of S-adenosylmethionine-dependent methyltransferase that targets the degradation of EZH2, preferentially induces apoptosis in various hematological malignancies, suggesting that EZH2 may be a new target for epigenetic treatment. Because PRC2 participates in epigenetic silencing of a subset of GATA-1 target genes during erythroid differentiation, inhibition of EZH2 may influence erythropoiesis. To explore this possibility, we evaluated the impact of DZNep on erythropoiesis. DZNep treatment significantly induced erythroid differentiation of K562 cells, as assessed by benzidine staining and quantitative RT-PCR analysis for representative erythroid-related genes, including globins. When we evaluated the effects of DZNep in human primary erythroblasts derived from cord blood CD34-positive cells, the treatment significantly induced erythroid-related genes, as observed in K562 cells, suggesting that DZNep induces erythroid differentiation. Unexpectedly, siRNA-mediated EZH2 knockdown had no significant effect on the expression of erythroid-related genes. Transcriptional profiling of DZNep-treated K562 cells revealed marked up-regulation of SLC4A1 and EPB42, previously reported as representative targets of the transcriptional corepressor ETO2. In addition, DZNep treatment reduced the protein level of ETO2. These data suggest that erythroid differentiation by DZNep may not be directly related to EZH2 inhibition but may be partly associated with reduced protein level of hematopoietic corepressor ETO2. These data provide a better understanding of the mechanism of action of DZNep, which may be exploited for therapeutic applications for hematological diseases, including anemia.


Asunto(s)
Adenosina/análogos & derivados , Diferenciación Celular/efectos de los fármacos , Células Eritroides/efectos de los fármacos , Metiltransferasas/antagonistas & inhibidores , Adenosina/farmacología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Eritroblastos/citología , Eritroblastos/efectos de los fármacos , Eritroblastos/metabolismo , Células Eritroides/citología , Células Eritroides/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Células K562 , Metiltransferasas/metabolismo , Proteínas Represoras/metabolismo , Proteínas Supresoras de Tumor/metabolismo
11.
Biochem Biophys Res Commun ; 454(1): 102-8, 2014 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-25450364

RESUMEN

Congenital sideroblastic anemia (CSA) is a hereditary disorder characterized by microcytic anemia and bone marrow sideroblasts. The most common form of CSA is attributed to mutations in the X-linked gene 5-aminolevulinic acid synthase 2 (ALAS2). ALAS2 is a mitochondrial enzyme, which utilizes glycine and succinyl-CoA to form 5-aminolevulinic acid (ALA), a crucial precursor in heme synthesis. Therefore, ALA supplementation could be an effective therapeutic strategy to restore heme synthesis in CSA caused by ALAS2 defects. In a preclinical study, we examined the effects of ALA in human erythroid cells, including K562 cells and human induced pluripotent stem cell-derived erythroid progenitor (HiDEP) cells. ALA treatment resulted in significant dose-dependent accumulation of heme in the K562 cell line. Concomitantly, the treatment substantially induced erythroid differentiation as assessed using benzidine staining. Quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis confirmed significant upregulation of heme-regulated genes, such as the globin genes [hemoglobin alpha (HBA) and hemoglobin gamma (HBG)] and the heme oxygenase 1 (HMOX1) gene, in K562 cells. Next, to investigate the mechanism by which ALA is transported into erythroid cells, quantitative RT-PCR analysis was performed on previously identified ALA transporters, including solute carrier family 15 (oligopeptide transporter), member (SLC15A) 1, SLC15A2, solute carrier family 36 (proton/amino acid symporter), member (SLC36A1), and solute carrier family 6 (neurotransmitter transporter), member 13 (SLC6A13). Our analysis revealed that SLC36A1 was abundantly expressed in erythroid cells. Thus, gamma-aminobutyric acid (GABA) was added to K562 cells to competitively inhibit SLC36A1-mediated transport. GABA treatment significantly impeded the ALA-mediated increase in the number of hemoglobinized cells as well as the induction of HBG, HBA, and HMOX1. Finally, small-interfering RNA-mediated knockdown of ALAS2 in HiDEP cells considerably decreased the expression of HBA, HBG, and HMOX1, and these expression levels were rescued with ALA treatment. In summary, ALA appears to be transported into erythroid cells mainly by SLC36A1 and is utilized to generate heme. ALA may represent a novel therapeutic option for CSA treatment, particularly for cases harboring ALAS2 mutations.


Asunto(s)
Ácido Aminolevulínico/farmacología , Anemia Sideroblástica/tratamiento farmacológico , Eritropoyesis/efectos de los fármacos , Enfermedades Genéticas Ligadas al Cromosoma X/tratamiento farmacológico , 5-Aminolevulinato Sintetasa/antagonistas & inhibidores , 5-Aminolevulinato Sintetasa/genética , 5-Aminolevulinato Sintetasa/metabolismo , Sistemas de Transporte de Aminoácidos/genética , Sistemas de Transporte de Aminoácidos/metabolismo , Anemia Sideroblástica/genética , Anemia Sideroblástica/metabolismo , Animales , Evaluación Preclínica de Medicamentos , Eritroblastos/citología , Eritroblastos/efectos de los fármacos , Eritroblastos/metabolismo , Eritropoyesis/genética , Eritropoyesis/fisiología , Técnicas de Silenciamiento del Gen , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/metabolismo , Hemo/biosíntesis , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Hemoglobina A/genética , Hemoglobina A/metabolismo , Hemoglobinas Anormales/genética , Hemoglobinas Anormales/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Células K562 , Ratones , Simportadores/genética , Simportadores/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Ácido gamma-Aminobutírico/farmacología
12.
Haematologica ; 99(11): 1686-96, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25150255

RESUMEN

The bone marrow microenvironment comprises multiple cell niches derived from bone marrow mesenchymal stem cells. However, the molecular mechanism of bone marrow mesenchymal stem cell differentiation is poorly understood. The transcription factor GATA2 is indispensable for hematopoietic stem cell function as well as other hematopoietic lineages, suggesting that it may maintain bone marrow mesenchymal stem cells in an immature state and also contribute to their differentiation. To explore this possibility, we established bone marrow mesenchymal stem cells from GATA2 conditional knockout mice. Differentiation of GATA2-deficient bone marrow mesenchymal stem cells into adipocytes induced accelerated oil-drop formation. Further, GATA2 loss- and gain-of-function analyses based on human bone marrow mesenchymal stem cells confirmed that decreased and increased GATA2 expression accelerated and suppressed bone marrow mesenchymal stem cell differentiation to adipocytes, respectively. Microarray analysis of GATA2 knockdowned human bone marrow mesenchymal stem cells revealed that 90 and 189 genes were upregulated or downregulated by a factor of 2, respectively. Moreover, gene ontology analysis revealed significant enrichment of genes involved in cell cycle regulation, and the number of G1/G0 cells increased after GATA2 knockdown. Concomitantly, cell proliferation was decreased by GATA2 knockdown. When GATA2 knockdowned bone marrow mesenchymal stem cells as well as adipocytes were cocultured with CD34-positive cells, hematopoietic stem cell frequency and colony formation decreased. We confirmed the existence of pathological signals that decrease and increase hematopoietic cell and adipocyte numbers, respectively, characteristic of aplastic anemia, and that suppress GATA2 expression in hematopoietic stem cells and bone marrow mesenchymal stem cells.


Asunto(s)
Diferenciación Celular/genética , Factor de Transcripción GATA2/genética , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Adipocitos/citología , Adipocitos/metabolismo , Animales , Médula Ósea , Proteínas de Ciclo Celular/genética , Microambiente Celular/genética , Factor de Transcripción GATA2/metabolismo , Expresión Génica , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Humanos , Ratones , Ratones Noqueados , Interferencia de ARN , ARN Interferente Pequeño/genética
14.
Hum Vaccin Immunother ; 19(1): 2165381, 2023 12 31.
Artículo en Inglés | MEDLINE | ID: mdl-36625832

RESUMEN

Herein, we report the case of a 22-year-old woman with hereditary spherocytosis (HS) whose condition worsened after administration of the coronavirus disease 2019 (COVID-19), mRNA vaccine 'BNT162b2 Pfizer-BioNTech.' The woman had been diagnosed with HS in 2005, and her condition remained stable until February 2021. In March 2021, she received the first dose of the above vaccine and experienced pain at the injection site. After the second dose in April 2021, she developed fever and general malaise. Investigations revealed progression of hemolysis, which improved after a few days. To the best of our knowledge, this is the first report of progression of hemolysis in a patient with HS after administration of the mRNA vaccine COVID-19, BNT162b2 'Pfizer-BioNTech.'


Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Humanos , Femenino , Adulto Joven , Adulto , Vacunas contra la COVID-19/efectos adversos , Vacuna BNT162 , Hemólisis , COVID-19/prevención & control , Vacunas de ARNm
18.
Biol Blood Marrow Transplant ; 17(7): 1093-7, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21277378

RESUMEN

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) is one of the highest-risk ALL groups. Whenever possible, patients with Ph(+)ALL should undergo allogeneic hematopoietic stem cell transplantation (HSCT) after induction of remission. Although unrelated cord blood transplantation (CBT) has become a common treatment in adult patients who lack a sibling donor, data on the efficacy of CBT for Ph(+)ALL are limited. We analyzed the clinical outcomes of 20 Ph(+)ALL patients who underwent CBT (n = 8) or unrelated bone marrow transplantation (BMT) (n = 12). The median age was 41 years (range, 17-55 years). All but one of the patients were treated with an imatinib-based regimen before HSCT, and 19 patients were in first complete remission (CR) and 1 patient was in second CR at the time of HSCT. Seventeen patients received a myeloablative conditioning regimen containing 12 Gy of total-body irradiation, and 3 received a reduced-intensity conditioning regimen. After a median of 26 months of follow-up, estimated 3-year overall and leukemia-free survival rates were 100% and 85%, respectively, after CBT, and 49% and 38%, respectively, after unrelated BMT. The CBT group had significantly better overall survival than the BMT group (P = .02). Although BCR-ABL transcript was detected in 4 of 8 CBT patients at transplantation, 7 patients remained in molecular CR. Our findings suggest that CBT may be a viable option as postinduction therapy for Ph(+)ALL in patients lacking a sibling donor.


Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirugía , Donantes de Tejidos , Trasplante Homólogo/métodos , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/sangre , Terapia Combinada , Trasplante de Células Madre de Sangre del Cordón Umbilical/estadística & datos numéricos , Femenino , Proteínas de Fusión bcr-abl/sangre , Enfermedad Injerto contra Huésped/epidemiología , Humanos , Estimación de Kaplan-Meier , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Agonistas Mieloablativos/uso terapéutico , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Inducción de Remisión , Estudios Retrospectivos , Acondicionamiento Pretrasplante/métodos , Resultado del Tratamiento , Irradiación Corporal Total , Adulto Joven
19.
Intern Med ; 60(6): 927-933, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33716255

RESUMEN

Spontaneous regression is rare in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). An 85-year-old man presented with pancytopenia and skin lesions, and the bone marrow exhibited 79.6% CD4+, CD56+, CD123+, and TCL-1+ abnormal cells, with a normal karyotype; he was thus diagnosed with BPDCN. While being followed without chemotherapy, he was admitted due to sepsis induced by Serratia marcescens, which was successfully treated with antibiotics. Notably, his blood cell counts improved, and the skin lesions disappeared. To our knowledge, this is the first reported case of spontaneous regression of BPDCN with a decrease in tumor cells in the bone marrow following sepsis.


Asunto(s)
Neoplasias Hematológicas , Trastornos Mieloproliferativos , Sepsis , Neoplasias Cutáneas , Anciano de 80 o más Años , Células Dendríticas , Humanos , Masculino , Serratia marcescens
20.
J Lab Physicians ; 11(4): 382-384, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31929708

RESUMEN

An 82-year-old male was admitted. Pancytopenia, a slightly low white blood cell count (3400/µL), and low levels of red blood cells (2.65 × 106/µL), hemoglobin (10.4 g/dL), and platelets (118,000/µL) were observed. Bone marrow aspiration was performed, revealing hypocellular bone marrow and normal blast levels (0.6%) with no dysplasia. G-banding chromosome analysis revealed the karyotype 45,X,-Y[3]/45, idem, t(10;18)(q26;q21)[13]/46,XY[4]. The patient was diagnosed with myelodysplastic syndrome, unclassified (MDS-U). This is the first case report demonstrating a patient with the chromosomal translocation, t(14;18)(q32;q21), which is extremely rare. This chromosomal aberration was critical for the diagnosis of MDS in this patient.

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