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O-linked N-acetylglucosamine transferase (OGT) critically regulates wide variety of biological processes such as gene expression, metabolism, stress response, signaling and proteostasis. In adult hematopoiesis, OGT is crucial for differentiation of B and T cells and the maintenance of hematopoietic stem cells (HSCs). However, a role for OGT in fetal liver (FL) hematopoiesis remains unknown. To investigate a role for OGT in FL hematopoiesis, we conditionally disrupted OGT in hematopoietic cells in developing FLs. Hematopoietic specific disruption of OGT resulted in embryonic lethality in late stage of gestation due to severe anemia and growth retardation. OGT loss led to profound reduction of differentiating erythroid cells and erythroid progenitors in FLs due to massive apoptosis. In addition, clonogenic capacity of FL cells was severely impaired by OGT loss. Interestingly, expression of BCL-XL, a well-known inhibitor of apoptosis in FL cells, dramatically decreased, and the levels of reactive oxygen species (ROS) were increased in OGT-deficient FL cells. Overexpression of Bcl-xL and reduction of ROS significantly restored the colony formation of OGT-deficient FL cells. This study revealed a novel role for OGT during embryogenesis, which ensures survival of FL hematopoietic cells partly by regulating Bcl-xL and oxidative phosphorylation.
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N-Acetilglucosaminiltransferases , Fosforilação Oxidativa , Camundongos , Animais , Espécies Reativas de Oxigênio/metabolismo , Diferenciação Celular , N-Acetilglucosaminiltransferases/genética , Fígado/metabolismoRESUMO
Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drives inv(3)/t(3;3) myeloid leukemias via structural rearrangement of an enhancer that upregulates transcription of EVI1. Here, we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 that is frequently present in inv(3)/t(3;3) acute myeloid leukemia (AML) and directly contributes to leukemic transformation. This EVI1 isoform is generated by oncogenic mutations in the core RNA splicing factor SF3B1, which is mutated in >30% of inv(3)/t(3;3) myeloid neoplasm patients and thereby represents the single most commonly cooccurring genomic alteration in inv(3)/t(3;3) patients. SF3B1 mutations are statistically uniquely enriched in inv(3)/t(3;3) myeloid neoplasm patients and patient-derived cell lines compared with other forms of AML and promote mis-splicing of EVI1 generating an in-frame insertion of 6 amino acids at the 3' end of the second zinc finger domain of EVI1. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells, and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21q26) allele resulted in generation of this novel EVI1 isoform in mice and hastened leukemogenesis in vivo. The mutant SF3B1 spliceosome depends upon an exonic splicing enhancer within EVI1 exon 13 to promote usage of a cryptic branch point and aberrant 3' splice site within intron 12 resulting in the generation of this isoform. These data provide a mechanistic basis for the frequent cooccurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).
Assuntos
Leucemia Mieloide Aguda , Proto-Oncogenes , Animais , Inversão Cromossômica , Cromossomos Humanos Par 3/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Leucemia Mieloide Aguda/patologia , Proteína do Locus do Complexo MDS1 e EVI1/genética , Camundongos , Proto-Oncogenes/genética , Fatores de Transcrição/metabolismoRESUMO
The epigenome regulates transcription of target genes through DNA methylation- or histone methylation/acetylation/phosphorylation/ubiquitination-mediated alteration of genomic function or chromatin conformation. Recent genomic studies have shown that multiple genes encoding epigenetic regulators are frequently and recurrently mutated in MDS, suggesting that epigenetic dysregulation is significantly associated with the molecular pathogenesis and clinical features of MDS. In this review, we will present our recent findings together with others, focusing on physiological molecular functions of epigenetic regulators recurrently mutated in MDS and on functional correlation between dysregulated epigenomic regulators and molecular pathogenesis/clinical features of MDS.
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Epigênese Genética , Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Metilação de DNA , Mutação , Histonas/metabolismoRESUMO
VEXAS syndrome is a new disease entity characterized by the presence of cytoplasmic vacuoles in blood cells, X-linked autoinflammatory symptoms, and somatic variants in UBA1, which encodes an E1 ubiquitin-activating enzyme. Around 30-50% of VEXAS syndrome patients have concurrent MDS. We and others have recently analyzed clinical and genetic features of MDS associated with VEXAS syndrome and found that most of these cases are categorized in the low-risk subgroup with low bone marrow blast percentages. MDS associated with VEXAS syndrome tended to involve a smaller number of genes and lower-risk genetic alterations than classical MDS. In addition, anemia in MDS associated with VEXAS syndrome with active inflammation before treatment tended to respond well to steroids. In this review, we will present our recent findings together with others, focusing on the new disease entity and pathophysiology of VEXAS syndrome and clinical/genetic features of associated MDS.
Assuntos
Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/genética , Enzimas Ativadoras de Ubiquitina/genéticaRESUMO
Regulation of genome-wide DNA methylation is fundamental for a variety of biological processes such as mammalian development, stem cell function, cellular proliferation/differentiation, and oncogenesis. Among the regulators of DNA methylation, ten-eleven translocation 2 (TET2) is one of the most frequently mutated genes in clonal hematopoiesis of indeterminate potential and in various hematological malignancies, underscoring a pivotal role for TET2 in blood homeostasis and hematopoietic transformation. TET2 oxidizes methylated cytosines to further modify cytosines, which behave as intermediates in active/passive DNA demethylation processes. TET2 itself associates with histone modifiers, thereby regulating histone modifications and expression of target genes. A number of studies have reported pleiotropic effects of TET2 on hematopoietic stem cell self-renewal, hematopoietic differentiation, genome instability and inflammatory response. Recent single-cell genomics studies have identified gene promoters as well as transcription factor binding sites as TET2-targeted genetic loci in which disruption of DNA methylation can fundamentally modify hematopoietic differentiation and promote leukemogenesis. TET2 mutations show convergent cooperativity with other disease alleles in signaling molecules, epigenetic modifiers, and spliceosome factors in hematopoietic transformation. Future studies focusing on the molecular basis of stem cell and immune regulation by TET2 loss will further deepen our understanding of the entire landscape of pathophysiology and molecular vulnerabilities of TET2-mutated hematological malignancies.
Assuntos
Transformação Celular Neoplásica/genética , Proteínas de Ligação a DNA/genética , Hematopoese/genética , Animais , Diferenciação Celular/genética , Metilação de DNA/genética , Humanos , Mutação/genética , Transdução de Sinais/genéticaRESUMO
Recent studies have reported that activation-induced cytidine deaminase (AID) and ten-eleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of TET2 occur in myeloid malignancies, and hematopoietic-specific loss of Tet2 induces aberrant hematopoietic stem cell (HSC) self-renewal/differentiation, implicating TET2 as a master regulator of normal and malignant hematopoiesis. Despite the functional link between AID and TET in epigenetic gene regulation, the role of AID loss in hematopoiesis and myeloid transformation remains to be investigated. Here, we show that Aid loss in mice leads to expansion of myeloid cells and reduced erythroid progenitors resulting in anemia, with dysregulated expression of Cebpa and Gata1, myeloid/erythroid lineage-specific transcription factors. Consistent with data in the murine context, silencing of AID in human bone marrow cells skews differentiation toward myelomonocytic lineage. However, in contrast to Tet2 loss, Aid loss does not contribute to enhanced HSC self-renewal or cooperate with Flt3-ITD to induce myeloid transformation. Genome-wide transcription and differential methylation analysis uncover the critical role of Aid as a key epigenetic regulator. These results indicate that AID and TET2 share common effects on myeloid and erythroid lineage differentiation, however, their role is nonredundant in regulating HSC self-renewal and in myeloid transformation.
Assuntos
Diferenciação Celular , Citidina Desaminase/fisiologia , Metilação de DNA , Células-Tronco Hematopoéticas/metabolismo , Animais , Linhagem da Célula , Autorrenovação Celular , Transformação Celular Neoplásica , Citidina Desaminase/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Dioxigenases , Células Eritroides/citologia , Inativação Gênica , Células-Tronco Hematopoéticas/citologia , Humanos , Camundongos , Células Mieloides/citologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/fisiologiaRESUMO
DNA methylation is one of the critical epigenetic modifications regulating various cellular processes such as differentiation or proliferation, and its dysregulation leads to disordered stem cell function or cellular transformation. The ten-eleven translocation (TET) gene family, initially found as a chromosomal translocation partner in leukemia, turned out to be a key enzyme for DNA demethylation. TET genes hydroxylate 5-methylcytosine to 5-hydroxymethylcytosine, which is then converted to unmodified cytosine through multiple mechanisms. Somatic mutations of the TET2 gene were reported in a variety of human hematological malignancies such as leukemia, myelodysplastic syndrome, and malignant lymphoma, suggesting a critical role for TET2 in hematopoiesis. The importance of the TET-mediated cytosine demethylation pathway is also underscored by a recurrent mutation of isocitrate dehydrogenase 1 (IDH1) and IDH2 in hematological malignancies, whose mutation inhibits TET function through a novel oncometabolite, 2-hydroxyglutarate. Studies using mouse models revealed that TET2 is critical for the function of hematopoietic stem cells, and disruption of TET2 results in the expansion of multipotent as well as myeloid progenitors, leading to the accumulation of premalignant clones. In addition to cytosine demethylation, TET proteins are involved in chromatin modifications and other cellular processes through the interaction with O-linked ß-N-acetylglucosamine transferase. In summary, TET2 is a critical regulator for hematopoietic stem cell homeostasis whose functional impairment leads to hematological malignancies. Future studies will uncover the whole picture of epigenetic and signaling networks wired with TET2, which will help to develop ways to intervene in cellular pathways dysregulated by TET2 mutations.
Assuntos
Proteínas de Ligação a DNA/fisiologia , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Hematopoese/genética , Proteínas Proto-Oncogênicas/fisiologia , Animais , Metilação de DNA , Dioxigenases , Neoplasias Hematológicas/genética , Humanos , MutaçãoRESUMO
VEXAS syndrome is a recently identified, adult-onset autoinflammatory disease caused by somatic mutations in UBA1. UBA1 is an X-linked gene encoding E1 ubiquitin activating enzyme and its mutation in hematopoietic stem and progenitor cells leads to their clonal expansion and myeloid-skewed differentiation. UBA1 mutations in VEXAS are clustered at the second methionine (p.Met41), eliminating UBA1b isoform translated from p.Met41. Loss of UBA1b impairs ubiquitination and activates innate immune pathways, leading to systemic autoinflammation manifested as recurrent fever, chondritis, pulmonary involvement, vasculitis, or neutrophilic dermatitis. VEXAS syndrome is frequently associated with hematological disorders such as myelodysplastic syndrome (MDS), plasma cell dyscrasia and venous thromboembolism. Macrocytic anemia/macrocytosis and vacuoles in myeloid/erythroid precursors are prominent features of VEXAS syndrome, and their presence in patients with autoinflammatory symptoms prompts physicians to screen for UBA1 variant. Treatment of VEXAS syndrome is challenging and no consistently effective therapies have been established. Anti-inflammation therapies including glucocorticoids and anti-interleukin-6 have shown limited efficacy, while azacytidine and JAK inhibitors such as ruxolitinib were found to induce favorable, mid-term responses. Hematopoietic stem cell transplantation is the only curative option for VEXAS and should be considered for younger, fit patients with poor prognostic factors or recalcitrant symptoms.
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Bloom syndrome (BS) is an autosomal recessive genetic disorder caused by variants in the BLM gene. BS is characterized by distinct facial features, elongated limbs, and various dermatological complications including photosensitivity, poikiloderma, and telangiectatic erythema. The BLM gene encodes a RecQ helicase critical for genome maintenance, stability, and repair, and a deficiency in functional BLM protein leads to genomic instability and high predisposition to various types of cancers, particularly hematological and gastrointestinal malignancies. Here, we report a case of BS with a previously unreported variant in the BLM gene. The patient was a 34-year-old woman who presented with short stature, prominent facial features, and a history of malignancies, including lymphoma, breast cancer, and myelodysplastic syndromes (MDS). She was initially treated with azacitidine for MDS and showed transient improvement, but eventually died at age of 35 due to progression of MDS. Genetic screening revealed compound heterozygous variants in the BLM gene, with a recurrent variant previously reported in BS in one allele and a previously unreported variant in the other allele. Based on her characteristic clinical features and the presence of heterozygous variants in the BLM gene, she was diagnosed with BS harboring compound heterozygous BLM variants.
Assuntos
Síndrome de Bloom , Síndromes Mielodisplásicas , RecQ Helicases , Humanos , Síndrome de Bloom/genética , Feminino , RecQ Helicases/genética , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Azacitidina/efeitos adversos , Azacitidina/uso terapêutico , Evolução Fatal , Mutação , HeterozigotoRESUMO
Erdheim-Chester disease (ECD) is a rare, non-Langerhans cell histiocytosis with diverse clinical features. It is characterized by systemic histiocyte infiltration of the bone, skin, central nervous system, lung, kidney, and cardiovascular system. Pericardial involvement is frequently revealed through either pericardial effusion or pericardial thickening in patients with ECD. Although most patients remain asymptomatic, progressive pericarditis, effusion, or cardiac tamponade may occur. Herein, we report a rare and unusual presentation of ECD in a 51-year-old man who experienced severe constrictive pericarditis. The patient presented with uncontrolled fluid retention and heart failure. After the diagnosis of ECD, interferon alpha treatment was administered. The patient recovered dramatically with decreased pleural and pericardial effusion, as well as improvements in the echocardiographic signs of constrictive pericarditis. Despite several therapeutic options described in the literature for managing ECD-related pericardial disease, a standard treatment has not been established. This report highlights the importance of early treatment based on accurate diagnosis of an unusual ECD complication.
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VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a new disease entity with autoinflammatory disorders (AID) driven by somatic variants in UBA1 that frequently co-exists with myelodysplastic syndromes (MDS). Clinicopathological and molecular features of Japanese cases with VEXAS-associated MDS remain elusive. We previously reported high prevalence of UBA1 variants in Japanese patients with relapsing polychondritis, in which 5 cases co-occurred with MDS. Here, we report clinicopathological and variant profiles of these 5 cases and 2 additional cases of MDS associated with VEXAS syndrome. Clinical characteristics of these cases included high prevalence of macrocytic anemia with marked cytoplasmic vacuoles in myeloid/erythroid precursors and low bone marrow (BM) blast percentages. All cases were classified as low or very low risk by the revised international prognostic scoring system (IPSS-R). Notably, 4 out of 7 cases showed significant improvement of anemia by treatment with prednisolone (PSL) or cyclosporin A (CsA), suggesting that an underlying inflammatory milieu induced by VEXAS syndrome may aggravate macrocytic anemia in VEXAS-associated MDS. Targeted deep sequencing of blood samples suggested that MDS associated with VEXAS syndrome tends to involve a smaller number of genes and lower risk genetic lesions than classical MDS.
Assuntos
População do Leste Asiático , Síndromes Mielodisplásicas , Humanos , Medula Óssea/patologia , População do Leste Asiático/genética , Mutação , Síndromes Mielodisplásicas/etnologia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , RiscoRESUMO
Background: Immune checkpoint inhibitors (ICIs) have been a breakthrough in cancer therapy. ICI therapy is generally better tolerated than cytotoxic chemotherapy; however, hematological adverse events (AEs) have not been fully analyzed. Hence, we performed a meta-analysis to evaluate the incidence and risk of ICI-related hematological AEs. Methods: A systematic literature search was performed using PubMed, EMBASE, Cochrane Library, and the Web of Science Core Collection. Phase III randomized controlled trials (RCTs) involving ICI combination regimens were selected. The experimental group received ICIs with systemic treatment, and the control group received only the same systemic treatment. Odds ratios (ORs) for anemia, neutropenia, and thrombocytopenia were calculated using a random-model meta-analysis. Results: We identified 29 RCTs with 20,033 patients. The estimated incidence rates for anemia of all grades and grades III-V were 36.5% (95% confidence interval (CI) 30.23 - 42.75) and 4.1% (95% CI 3.85 - 4.42), respectively. The incidence of neutropenia (all grades 29.7%, grades III-V 5.3%) and thrombocytopenia (all grades 18.0%, grades III-V 1.6%) was also calculated. Conclusion: Treatment with ICIs seemed unlikely to increase the incidence of anemia, neutropenia, and thrombocytopenia in all grades. However, programmed cell death-1 receptor ligand inhibitors significantly increased the risk of grades III-V thrombocytopenia (OR 1.53; 95% CI 1.11 - 2.11). Further research is needed to examine the potential risk factors.
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Despite recent advances in the treatment of acute myeloid leukemia (AML), there has been limited success in targeting surface antigens in AML, in part due to shared expression across malignant and normal cells. Here, high-density immunophenotyping of AML coupled with proteogenomics identified unique expression of a variety of antigens, including the RNA helicase U5 snRNP200, on the surface of AML cells but not on normal hematopoietic precursors and skewed Fc receptor distribution in the AML immune microenvironment. Cell membrane localization of U5 snRNP200 was linked to surface expression of the Fcγ receptor IIIA (FcγIIIA, also known as CD32A) and correlated with expression of interferon-regulated immune response genes. Anti-U5 snRNP200 antibodies engaging activating Fcγ receptors were efficacious across immunocompetent AML models and were augmented by combination with azacitidine. These data provide a roadmap of AML-associated antigens with Fc receptor distribution in AML and highlight the potential for targeting the AML cell surface using Fc-optimized therapeutics.
Assuntos
Leucemia Mieloide Aguda , Receptores de IgG , Humanos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Antígenos de Superfície , Leucemia Mieloide Aguda/tratamento farmacológico , Receptores Fc/metabolismo , Receptores de IgG/metabolismo , Ribonucleoproteínas Nucleares Pequenas , Microambiente TumoralRESUMO
Only limited data are available regarding the relationship between blood concentration of tacrolimus and its efficacy in preventing acute graft-versus-host disease (aGVHD). We retrospectively evaluated the effects of the whole blood concentration of tacrolimus, which was measured by an automated microparticle enzyme immunoassay, early after allogeneic hematopoietic stem cell transplantation (HSCT) upon the development of aGVHD. Sixty patients, who underwent allogeneic HSCT from serologically human-leukocyte antigen-matched unrelated donors and received continuous infusion of tacrolimus with short-term methotrexate for GVHD prophylaxis, were included in this study. The target range of the blood concentration of tacrolimus was set at 10 to 20 ng/mL, and the level was maintained within this range in all patients. However, the mean blood concentration of tacrolimus during the third week after HSCT was significantly associated with the grades of aGVHD (17.3 ± 2.1 in patients with grades 0-I vs 15.9 ± 2.8 in II-IV and 14.8 ± 2.1 in III-IV; P < .05 and <.01, respectively). Multivariate analysis also demonstrated that higher age (≥35) of donor (odds ratio [OR] = 4.28) and lower mean blood concentrations of tacrolimus during the second (OR = 0.75; 95% confidence interval [CI]: 0.58-0.98) and third weeks (OR = 0.76; 95% CI: 0.58-0.98) after HSCT were significant risk factors for grades II-IV aGVHD (P < .05). We conclude that the early posttransplantation blood concentration of tacrolimus had a significant impact on the development of moderate-to-severe aGVHD after allogeneic HSCT from an unrelated donor.
Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Tacrolimo/administração & dosagem , Tacrolimo/farmacologia , Doadores de Tecidos , Doença Aguda , Adolescente , Adulto , Fatores Etários , Criança , Feminino , Neoplasias Hematológicas/terapia , Humanos , Masculino , Metotrexato/administração & dosagem , Metotrexato/farmacocinética , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Transplante HomólogoRESUMO
Objectives: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only curative treatment for myelodysplastic syndromes (MDS), although predicting post-transplant outcomes remains inconclusive. This study evaluated patients who underwent allo-HCT for MDS to identify prognostic factors and develop a clinical risk model.Methods: We evaluated 55 patients between June 2000 and March 2015 to identify prognostic factors and develop a model for three-year overall survival (OS) and event-free survival (EFS). Cox regression analysis was performed on four factors: age ≥55 years; Hematopoietic Cell Transplant-Comorbidity Index >2; intermediate or worse cytogenetic status based on revised International Prognostic Scoring System; and unrelated donor status associated with poor OS in the univariate analysis. A clinical risk model was constructed using the sum of the regression coefficients and evaluated using receiver operating characteristic analysis and five-fold cross-validation.Results: Patient median age was 51 (range: 30-67) years. Median follow-up was 45.8 (range: 1.27-193) months; the three-year OS and EFS rates were 61.8% and 56.4%, respectively. The areas under the curves (AUCs) for OS and EFS were 0.738 and 0.778, respectively, and the average AUC for 50 times five-fold cross-validation were 0.711 and 0.723 for three-year OS and EFS, respectively.Conclusion: A four-clinical-risk-factor model that could effectively predict post-transplantation outcomes and help decision-making in MDS treatment was developed.
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Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Transplante HomólogoAssuntos
Proteínas de Ligação a DNA/genética , Mutação , Células Progenitoras Mieloides/metabolismo , Proteínas Proto-Oncogênicas/genética , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Proteínas de Ligação a DNA/metabolismo , Dioxigenases , Imunofenotipagem , Camundongos , Camundongos Knockout , Fenótipo , Proteínas Proto-Oncogênicas/metabolismoRESUMO
We conducted population pharmacokinetic (PPK) analysis and Monte Carlo simulations to determine the appropriate prophylactic dose of fluconazole to prevent invasive candidiasis in patients with hematological malignancies. Patients receiving chemotherapy or hematopoietic stem cell transplantation at Yokohama City University Hospital between November 2018 and March 2020 were included. Additionally, patients receiving oral fluconazole for prophylaxis were recruited. We set the free area under the curve/minimum inhibitory concentration (MIC) = 50 as the target and determined the largest MIC (breakpoint MIC) that could achieve more than 90% probability of target attainment. The blood fluconazole concentration of 54 patients (119 points) was used for PPK analysis. The optimal model was the one-compartment model with first-order administration and first-order elimination incorporating creatinine clearance (CLcr) as a covariate of clearance and body weight as a covariate of distribution volume. We conducted Monte Carlo simulation with fluconazole at 200 mg/day or 400 mg/day dosing schedules and patient body weight and CLcr ranging from 40 to 70 kg and 40-140 mL/min, respectively. The breakpoint MICs on the first dosing day and at steady state were 0.5-1.0 µg/mL and 1.0-2.0 µg/mL for 200 mg/day and 1.0-2.0 µg/mL and 2.0-4.0 µg/mL for 400 mg/day, respectively. The recommended dose was 400-700 mg/day for the loading dose and 200-400 mg/day for the maintenance dose. Our findings suggest that the optimal prophylactic dose of fluconazole in hematological malignancy patients depends on CLcr and body weight, and a sufficient loading and maintenance dose may be needed to completely prevent invasive candidiasis.
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O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is a unique enzyme introducing O-GlcNAc moiety on target proteins, and it critically regulates various cellular processes in diverse cell types. However, its roles in hematopoietic stem and progenitor cells (HSPCs) remain elusive. Here, using Ogt conditional knockout mice, we show that OGT is essential for HSPCs. Ogt is highly expressed in HSPCs, and its disruption induces rapid loss of HSPCs with increased reactive oxygen species and apoptosis. In particular, Ogt-deficient hematopoietic stem cells (HSCs) lose quiescence, cannot be maintained in vivo, and become vulnerable to regenerative and competitive stress. Interestingly, Ogt-deficient HSCs accumulate defective mitochondria due to impaired mitophagy with decreased key mitophagy regulator, Pink1, through dysregulation of H3K4me3. Furthermore, overexpression of PINK1 restores mitophagy and the number of Ogt-deficient HSCs. Collectively, our results reveal that OGT critically regulates maintenance and stress response of HSCs by ensuring mitochondrial quality through PINK1-dependent mitophagy.
Assuntos
Células-Tronco Hematopoéticas/metabolismo , Histonas/metabolismo , Mitocôndrias/metabolismo , Mitofagia , N-Acetilglucosaminiltransferases/metabolismo , Proteínas Quinases/metabolismo , Acetilglucosamina/metabolismo , Animais , Apoptose , Ciclo Celular , Linhagem Celular , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , N-Acetilglucosaminiltransferases/genética , Espécies Reativas de Oxigênio/metabolismo , Estresse FisiológicoRESUMO
Recent genomics studies have revealed that clonal hematopoietic expansion due to recurrent somatic mutations in hematopoietic cells are common in older people without evidence of hematological malignancies. This phenomenon, termed clonal hematopoiesis of indeterminate potential (CHIP), is associated with greater risk for hematological malignancy and cardiovascular diseases, leading to decreased overall survival of the affected individuals. The most frequently mutated genes in CHIP cases include genes associated with epigenetic modification, cell signaling, DNA damage response and RNA splicing, which are all recurrently mutated in myeloid malignancies. Recent findings suggest that these genetic alleles exert pleiotropic effects on hematopoietic stem cell (HSC) functions, transcriptional regulations, DNA damage responses and resistance to cellular stresses. Recent studies have uncovered the clinical relevance of CHIP in various settings during the management of hematological malignancies. Elucidating overall picture of clonal evolution based on CHIP will help developing preventive measures and novel treatments for hematological malignancies.
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Doenças Cardiovasculares/metabolismo , Hematopoiese Clonal , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hematológicas/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Doenças Cardiovasculares/patologia , Neoplasias Hematológicas/patologia , Células-Tronco Hematopoéticas/patologia , HumanosRESUMO
Acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) with both inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and monosomy 7 defines an extremely aggressive myeloid cancer whose molecular pathogenesis and optimal therapeutic strategy still remain unclear. We established a new MDS/AML cell line, YCU-AML1, and its patient-derived xenograft (PDX) model from a high-risk MDS patient who later transformed into AML harboring both t(3;3)(q21;q26.2) and monosomy 7. YCU-AML1 cells propagated in co-culture system with stromal cells in granulocyte macrophage colony-stimulating factor (GM-CSF)-dependent manner. CD34+ bone marrow cells derived from our PDX model showed high EVI1 and low GATA2 expression. Moreover, mutational profile of our MDS/AML model was consistent with recently published mutational spectrum of myeloid malignancies with inv(3)/t(3;3). These data suggest that YCU-AML1 cells and its MDS/AML model strongly mimics a high-risk human myeloid cancer with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and monosomy 7 in terms of both clinical phenotype and molecular basis. We believe our model can be used as a feasible tool to further explore molecular pathogenesis and novel treatment strategy of high-risk MDS/AML with t(3;3)(q21;q26.2) and monosomy 7.