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ABSTRACT: BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive core ATPases of the chromatin remodeling BAF (BRG1/BRM-associated factor) complexes. They enable transcription factors/cofactors to access enhancers/promoter and modulate gene expressions responsible for cell growth and differentiation of acute myeloid leukemia (AML) stem/progenitor cells. In AML with MLL1 rearrangement (MLL1r) or mutant NPM1 (mtNPM1), although menin inhibitor (MI) treatment induces clinical remissions, most patients either fail to respond or relapse, some harboring menin mutations. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induces differentiation and lethality in AML cells with MLL1r or mtNPM1, concomitantly causing perturbed chromatin accessibility and repression of c-Myc, PU.1, and CDK4/6. Cotreatment with FHD-286 and decitabine, BET inhibitor (BETi) or MI, or venetoclax synergistically induced in vitro lethality in AML cells with MLL1r or mtNPM1. In models of xenografts derived from patients with AML with MLL1r or mtNPM1, FHD-286 treatment reduced AML burden, improved survival, and attenuated AML-initiating potential of stem-progenitor cells. Compared with each drug, cotreatment with FHD-286 and BETi, MI, decitabine, or venetoclax significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as a promising therapy for AML with MLL1r or mtNPM1.
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ADN Helicasas , Leucemia Mieloide Aguda , Proteínas Nucleares , Proteínas Proto-Oncogénicas , Factores de Transcripción , Animales , Humanos , Ratones , Proteínas que Contienen Bromodominio , Línea Celular Tumoral , ADN Helicasas/antagonistas & inhibidores , ADN Helicasas/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/genética , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/metabolismo , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleofosmina , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Genetic mutations in the isocitrate dehydrogenase (IDH) gene that result in a pathological enzymatic activity to produce oncometabolite have been detected in acute myeloid leukemia (AML) patients. While specific inhibitors that target mutant IDH enzymes and normalize intracellular oncometabolite level have been developed, refractoriness and resistance has been reported. Since acquisition of pathological enzymatic activity is accompanied by the abrogation of the crucial WT IDH enzymatic activity in IDH mutant cells, aberrant metabolism in IDH mutant cells can potentially persist even after the normalization of intracellular oncometabolite level. Comparisons of isogenic AML cell lines with and without IDH2 gene mutations revealed two mutually exclusive signalings for growth advantage of IDH2 mutant cells, STAT phosphorylation associated with intracellular oncometabolite level and phospholipid metabolic adaptation. The latter came to light after the oncometabolite normalization and increased the resistance of IDH2 mutant cells to arachidonic acid-mediated apoptosis. The release of this metabolic adaptation by FDA-approved anti-inflammatory drugs targeting the metabolism of arachidonic acid could sensitize IDH2 mutant cells to apoptosis, resulting in their eradication in vitro and in vivo. Our findings will contribute to the development of alternative therapeutic options for IDH2 mutant AML patients who do not tolerate currently available therapies.
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Leucemia Mieloide Aguda , Humanos , Ácido Araquidónico/uso terapéutico , Mutación , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Isocitrato Deshidrogenasa/metabolismoRESUMEN
BACKGROUND: Ivosidenib is primarily metabolized by CYP3A4; however, it induces CYP450 isozymes, including CYP3A4 and CYP2C9, whereas it inhibits drug transporters, including P-glycoprotein. Patients with acute myeloid leukemia are at risk of invasive fungal infections, and therefore posaconazole and voriconazole are commonly used in this population. Voriconazole is a substrate of CYP2C9, CYP2C19, and CYP3A4; therefore, concomitant ivosidenib may result in decreased serum concentrations. Although posaconazole is a substrate of P-glycoprotein, it is metabolized primarily via UDP glucuronidation; thus, the impact of ivosidenib on posaconazole exposure is unknown. METHODS: Patients treated with ivosidenib and concomitant triazole with at least one serum trough level were included. Subtherapeutic levels were defined as posaconazole <700 ng/mL and voriconazole <1.0 µg/mL. The incidences of breakthrough invasive fungal infections and QTc prolongation were identified at least 5 days after initiation of ivosidenib with concomitant triazole. RESULTS: Seventy-eight serum triazole levels from 31 patients receiving ivosidenib-containing therapy and concomitant triazole were evaluated. Of the 78 concomitant levels, 47 (60%) were subtherapeutic (posaconazole: n = 20 of 43 [47%]; voriconazole: n = 27 of 35 [77%]). Compared to levels drawn while patients were off ivosidenib, median triazole serum levels during concomitant ivosidenib were significantly reduced. There was no apparent increase in incidence of grade 3 QTc prolongation with concomitant azole antifungal and ivosidenib 500 mg daily. CONCLUSIONS: This study demonstrated that concomitant ivosidenib significantly reduced posaconazole and voriconazole levels. Voriconazole should be avoided, empiric high-dose posaconazole (>300 mg/day) may be considered, and therapeutic drug monitoring is recommended in all patients receiving concomitant ivosidenib.
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Glicina , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Piridinas , Triazoles , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Triazoles/administración & dosificación , Triazoles/uso terapéutico , Triazoles/farmacocinética , Masculino , Femenino , Persona de Mediana Edad , Anciano , Síndromes Mielodisplásicos/tratamiento farmacológico , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Piridinas/farmacocinética , Glicina/análogos & derivados , Glicina/uso terapéutico , Glicina/administración & dosificación , Voriconazol/uso terapéutico , Voriconazol/administración & dosificación , Anciano de 80 o más Años , Interacciones Farmacológicas , Adulto , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Antineoplásicos/efectos adversosRESUMEN
The majority of RUNX1 mutations in acute myeloid leukemia (AML) are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared with AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1, and c-Myc. Compared with AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. Homoharringtonine treatment repressed enhancers and their BRD4 occupancy and was associated with reduced levels of c-Myc, c-Myb, MCL1, and Bcl-xL. Consistent with this, cotreatment with omacetaxine and venetoclax or BET inhibitor induced synergistic in vitro lethality in AML expressing mtRUNX1. Compared with each agent alone, cotreatment with omacetaxine and venetoclax or BET inhibitor also displayed improved in vivo anti-AML efficacy, associated with improved survival of immune-depleted mice engrafted with AML cells harboring mtRUNX1. These findings highlight superior efficacy of omacetaxine-based combination therapies for AML harboring mtRUNX1.
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Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Homoharringtonina/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de la Síntesis de la Proteína/farmacología , Sulfonamidas/farmacología , Línea Celular Tumoral , Sinergismo Farmacológico , Humanos , Leucemia Mieloide Aguda/genética , Mutación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidoresRESUMEN
There is a growing body of evidence that therapy-related myeloid neoplasms (t-MNs) with driver gene mutations arise in the background of clonal hematopoiesis (CH) under the positive selective pressure of chemo- and radiation therapies. Uncovering the exposure relationships that provide selective advantage to specific CH mutations is critical to understanding the pathogenesis and etiology of t-MNs. In a systematic analysis of 416 patients with t-MN and detailed prior exposure history, we found that TP53 mutations were significantly associated with prior treatment with thalidomide analogs, specifically lenalidomide. We demonstrated experimentally that lenalidomide treatment provides a selective advantage to Trp53-mutant hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo, the effect of which was specific to Trp53-mutant HSPCs and was not observed in HSPCs with other CH mutations. Because of the differences in CK1α degradation, pomalidomide treatment did not provide an equivalent level of selective advantage to Trp53-mutant HSPCs, providing a biological rationale for its use in patients at high risk for t-MN. These findings highlight the role of lenalidomide treatment in promoting TP53-mutated t-MNs and offer a potential alternative strategy to mitigate the risk of t-MN development.
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Neoplasias Primarias Secundarias , Talidomida , Humanos , Lenalidomida/farmacología , Talidomida/efectos adversos , Células Madre Hematopoyéticas/metabolismo , Genes p53 , Mutación , Neoplasias Primarias Secundarias/etiología , Neoplasias Primarias Secundarias/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Patients with relapsed acute myeloid leukemia (rAML) experience dismal outcomes. We performed a comprehensive analysis of patients with rAML to determine the genetic dynamics and survival predictive factors. We analyzed 875 patients with newly diagnosed AML who received intensive treatment (IT) or low-intensity treatment (LIT). Of these patients, 197 experienced subsequent rAML. Data was available for 164 patients, with a median time from CR/CRi to relapse of 6.5 months. Thirty-five of the 164 patients (21%) experienced relapse after allogeneic hematopoietic stem cell transplantation (alloSCT). At relapse mutations in genes involved in pathway signaling tended to disappear, whereas clonal hematopoiesis-related mutations or TP53 tended to persist. Patients with normal karyotypes tended to acquire cytogenetic abnormalities at relapse. Patients treated with IT had a higher emergence rate of TP53 mutations (16%), compared to patients treated with LIT (1%, P = 0.009). The overall response rates were 38% and 35% for patients treated with salvage IT or LIT, respectively. Seventeen patients (10%) underwent alloSCT after salvage therapy. The median overall survival (OS) duration after relapse was 5.3 months, with a 1-year OS rate of 17.6%. Complex karyotype (hazard ratio [HR] = 2.14, P < 0.001), a KMT2A rearrangement (HR = 3.52, P = 0.011), time in remission < 12 months (HR = 1.71, P = 0.011), and an elevated white blood cell count at relapse (HR = 2.38, P = 0.005) were independent risk factors for OS duration. More effective frontline and maintenance therapies are warranted to prevent rAML.
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This study examined the seasonal and diurnal variations in soil respiration rates (RS) during a growing season at the treeline ecotone (2,800 m) and the lower distribution limit (1,600 m) of subalpine forests on a volcanic mountain in Japan. The aboveground biomass, the total RS during the growing season, and the RS per day during the growing season were lower at 2,800 m than those at 1,600 m. Seasonal RS variations positively correlated with those of soil and air temperatures at both elevations, and this tendency was more apparent at 1,600 m than 2,800 m. The mean volumetric soil water content (WS) during the growing season was much lower at 2,800 m than 1,600 m because of the scoria substrate at 2,800 m. The monthly mean diel cycle of RS was positively correlated with the soil temperature at each elevation every month, whereas that at 1,600 m was negatively correlated with that of the WS. The RS at 2,800 m decreased during the daytime especially in August, despite no changes in the WS. The decrease in RS after precipitation at 1,600 m was higher than that at 2,800 m. Seasonal and diurnal RS variations could be reproduced from soil and air temperatures, and WS. Estimating soil respiration rate from these variables will help understand the future carbon budget of forests due to global warming.
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Frecuencia Respiratoria , Suelo , Suelo/química , Estaciones del Año , Bosques , Temperatura , ChinaRESUMEN
Chronic myelomonocytic leukaemia (CMML) is a haematological disorder with high risk of transformation to acute myeloid leukaemia (AML). To characterize the phenotypic and genomic patterns of CMML progression, we evaluated a cohort of 189 patients with AML evolving from CMML. We found that transformation occurs through distinct trajectories characterized by genomic profiles and clonal evolution: monocytic (Mo-AML, 53%), immature myeloid (My-AML, 43%) or erythroid (Ery-AML, 2%). Mo-AML, characterized by expansion of monoblasts and promonocytes (low CD34, CD117 expression; high CD14, CD33, CD56 and CD64 expression), were defined by SRSF2, TET2 and RAS pathway mutation co-dominance and were more likely to evolve from SRSF2-TET2 co-mutant CMML through emergence/expansion of RAS pathway mutant clones. Conversely, My-AML, characterized by expansion of immature myeloid blasts (high frequency of CD34, CD38, CD117; low frequency of CD14, CD64 and CD56 expression) were less likely to exhibit SRSF2-TET2 co-mutations or RAS pathway mutations and had higher frequency of CEBPA mutations. Ery-AML was defined by complex karyotypes and TP53 mutations. A trend towards improved OS and EFS with hypomethylating agent-venetoclax combination was observed in My-AML, but not Mo-AML. These findings define distinct progression of CMML and set the basis for future studies evaluating the role of phenotype-specific therapeutics.
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Leucemia Mieloide Aguda , Leucemia Mielomonocítica Crónica , Humanos , Leucemia Mielomonocítica Crónica/genética , Mutación , Leucemia Mieloide Aguda/genética , FenotipoRESUMEN
Although clonal hematopoiesis (CH) can precede the development of acute myeloid leukemia (AML), it can also persist after achieving remission. Long-term clonal dynamics and clinical implications of persistent CH are not well understood. Here, we studied the prevalence, dynamics, and clinical implications of postremission CH in 164 AML patients who attained complete remission after induction chemotherapies. Postremission CH was identified in 79 (48%) patients. Postremission CH persisted long term in 91% of the trackable patients despite treatment with various types of consolidation and maintenance therapies. Postremission CH was eradicated in 20 out of 21 (95%) patients who underwent allogeneic stem cell transplant. Although patients with postremission CH as a group had comparable hematopoiesis with those without it, patients with persistent TET2 mutations showed significant neutropenia long term. Postremission CH had little impact on relapse risk, nonrelapse mortality, and incidence of atherosclerotic cardiovascular disease, although the clinical impact of post-CR CH was heterogeneous among different mutations. These data suggest that although residual clonal hematopoietic stem cells are generally resistant to consolidation and maintenance therapies, they retain the ability to maintain normal hematopoiesis and have little impact on clinical outcomes. Larger study is needed to dissect the gene-specific heterogeneity.
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Hematopoyesis Clonal , Leucemia Mieloide Aguda/genética , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Proteínas de Unión al ADN/genética , Dioxigenasas/genética , Femenino , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Inducción de Remisión , Trasplante de Células Madre , Adulto JovenRESUMEN
With advances in high-throughput, large-scale in vivo measurement and genome modification techniques at the single-nucleotide level, there is an increasing demand for the development of new technologies for the flexible design and control of cellular systems. Computer-aided design is a powerful tool to design new cells. Whole-cell modeling aims to integrate various cellular subsystems, determine their interactions and cooperative mechanisms, and predict comprehensive cellular behaviors by computational simulations on a genome-wide scale. It has been applied to prokaryotes, yeasts, and higher eukaryotic cells, and utilized in a wide range of applications, including production of valuable substances, drug discovery, and controlled differentiation. Whole-cell modeling, consisting of several thousand elements with diverse scales and properties, requires innovative model construction, simulation, and analysis techniques. Furthermore, whole-cell modeling has been extended to multiple scales, including high-resolution modeling at the single-nucleotide and single-amino acid levels and multicellular modeling of tissues and organs. This review presents an overview of the current state of whole-cell modeling, discusses the novel computational and experimental technologies driving it, and introduces further developments toward multihierarchical modeling on a whole-genome scale.
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Modelos Biológicos , Biología de Sistemas , Biología de Sistemas/métodos , Genoma/genética , Simulación por Computador , NucleótidosRESUMEN
Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) has a very poor prognosis. Determinants of clinical outcomes and optimal treatment remain uncertain. We retrospectively reviewed 108 cases of AML with inv(3)/t(3;3) and evaluated clinicopathological characteristics and clinical outcomes: 53 newly diagnosed (ND) AML and 55 relapsed/refractory (R/R) AML. Median age was 55 years. White blood cell (WBC) count ≥20x109/L and platelet count ≥140x109/L was observed in 25% and 32% of ND patients, respectively. Anomalies involving chromosome 7 were identified in 56% of patients. The most frequently mutated genes were SF3B1, PTPN11, NRAS, KRAS and ASXL1. In ND patients, the composite complete remission (CRc) rate was 46% overall; 46% with high-intensity treatments and 47% with lowintensity treatments. The 30-day mortality was 14% and 0%, with high- and low-intensity treatment, respectively. In R/R patients, the CRc rate was 14%. Venetoclax based-regimens were associated with a CRc rate of 33%. The 3-year overall survival (OS) was 8.8% and 7.1% in ND and R/R patients, respectively. The 3-year cumulative incidence of relapse was 81.7% overall. Older age, high WBC, high peripheral blast count, secondary AML and KRAS, ASXL1, DNMT3A mutations were associated with worse OS in univariable analyses. The 5-year OS rates were 44% and 6% with or without hematopoietic stem cell transplantation in CR1, respectively. AML with inv(3)/t(3;3) is associated with low CR rates, very high risk of relapse and dismal long-term survival. Intensive chemotherapy and hy pomethylating agents provide similar rates of remission and patients achieving CR benefit from hematopoietic stem cell transplantation in first CR.
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Leucemia Mieloide Aguda , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Proteínas Proto-Oncogénicas p21(ras)/genética , Translocación Genética , Inversión Cromosómica , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Factores de Transcripción/genética , PronósticoRESUMEN
AMP deaminase 2 (AMPD2) has been thought to play an important role in energy homeostasis and immuno-oncology, while selective AMPD2 inhibitors are highly demanded to clarify the physiological function of AMPD2. In this report, we describe selective AMPD2 inhibitors inducing allosteric modulation. Based on hypothesis that compounds that exhibit increased inhibition by preincubation would cause conformational change of the enzyme, starting from HTS hit compound 4, we discovered compound 8 through the SAR study. From X-ray structural information of 8, this chemical series has a novel mechanism of action that changes the substrate pocket to prevent AMP from binding. Further elaboration of compound 8 led to the tool compound 21 which exhibited potent inhibitory activity of AMPD2 in ex vivo evaluation of mouse liver.
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AMP Desaminasa , Ratones , Animales , AMP Desaminasa/metabolismoRESUMEN
Breast cancer metastasis is the leading cause of cancer-related deaths. Hypoxia in the tumor mass is believed to trigger cell migration, which is involved in a crucial process of breast cancer metastasis. However, the molecular mechanisms underlying aggressive behavior under hypoxic conditions have not been fully elucidated. Here, we demonstrate the significant motility of MDA-MB-231 cells cultured under hypoxic conditions compared to that of cells cultured under normoxic conditions. MDA-MB-231 cells under hypoxic conditions showed a significant increase in Na+/H+ exchanger isoform 1 (NHE1) expression level, which was observed to co-locate in lamellipodia formation. Inhibition of NHE1 significantly suppressed the intracellular pH and the expression of mesenchymal markers, thereby blocking the high migration activity in hypoxia. Moreover, treatment with ciglitazone, a potent and selective peroxisome proliferator-activated receptor γ (PPARγ) agonist, modulated hypoxia-enhanced motion in cells via the repression of NHE1. These findings highlight that NHE1 is required for migratory activity through the enhancement of epithelial-mesenchymal transition (EMT) in MDA-MB-231 cells under hypoxic conditions, and we propose new drug repurposing strategies targeting hypoxia based on NHE1 suppression by effective usage of PPARγ agonists.
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Neoplasias de la Mama/metabolismo , Intercambiador 1 de Sodio-Hidrógeno/metabolismo , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Transición Epitelial-Mesenquimal/fisiología , Femenino , Humanos , Modelos Biológicos , PPAR gamma/agonistas , Transducción de Señal/efectos de los fármacos , Tiazolidinedionas/farmacología , Hipoxia Tumoral/fisiología , Microambiente Tumoral/fisiologíaRESUMEN
Malignant neoplasms evolve in response to changes in oncogenic signalling. Cancer cell plasticity in response to evolutionary pressures is fundamental to tumour progression and the development of therapeutic resistance. Here we determine the molecular and cellular mechanisms of cancer cell plasticity in a conditional oncogenic Kras mouse model of pancreatic ductal adenocarcinoma (PDAC), a malignancy that displays considerable phenotypic diversity and morphological heterogeneity. In this model, stochastic extinction of oncogenic Kras signalling and emergence of Kras-independent escaper populations (cells that acquire oncogenic properties) are associated with de-differentiation and aggressive biological behaviour. Transcriptomic and functional analyses of Kras-independent escapers reveal the presence of Smarcb1-Myc-network-driven mesenchymal reprogramming and independence from MAPK signalling. A somatic mosaic model of PDAC, which allows time-restricted perturbation of cell fate, shows that depletion of Smarcb1 activates the Myc network, driving an anabolic switch that increases protein metabolism and adaptive activation of endoplasmic-reticulum-stress-induced survival pathways. Increased protein turnover renders mesenchymal sub-populations highly susceptible to pharmacological and genetic perturbation of the cellular proteostatic machinery and the IRE1-α-MKK4 arm of the endoplasmic-reticulum-stress-response pathway. Specifically, combination regimens that impair the unfolded protein responses block the emergence of aggressive mesenchymal subpopulations in mouse and patient-derived PDAC models. These molecular and biological insights inform a potential therapeutic strategy for targeting aggressive mesenchymal features of PDAC.
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Mesodermo/patología , Neoplasias Pancreáticas/patología , Animales , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Estrés del Retículo Endoplásmico/genética , Femenino , Genes myc , Genes ras , Humanos , MAP Quinasa Quinasa 4/metabolismo , Sistema de Señalización de MAP Quinasas , Masculino , Mesodermo/metabolismo , Ratones , Mosaicismo , Proteína Oncogénica p55(v-myc)/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Proteolisis , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteína SMARCB1/deficiencia , Proteína SMARCB1/metabolismo , Transcriptoma/genética , GemcitabinaRESUMEN
Cerebrospinal fluid (CSF) plays an important role in the homeostasis of the brain. We previously reported that CSF major glycoproteins are biosynthesized in the brain, i.e., lipocalin-type prostaglandin D2 synthase (L-PGDS) and transferrin isoforms carrying unique glycans. Although these glycoproteins are secreted from distinct cell types, their CSF levels have been found to be highly correlated with each other in cases of neurodegenerative disorders. The aim of this study was to examine these marker levels and their correlations in other neurological diseases, such as depression and schizophrenia, and disorders featuring abnormal CSF metabolism, including spontaneous intracranial hypotension (SIH) and idiopathic normal pressure hydrocephalus (iNPH). Brain-derived marker levels were found to be highly correlated with each other in the CSF of depression and schizophrenia patients. SIH is caused by CSF leakage, which is suspected to induce hypovolemia and a compensatory increase in CSF production. In SIH, the brain-derived markers were 2-3-fold higher than in other diseases, and, regardless of their diverse levels, they were found to be correlated with each other. Another abnormality of the CSF metabolism, iNPH, is possibly caused by the reduced absorption of CSF, which secondarily induces CSF accumulation in the ventricle; the excess CSF compresses the brain's parenchyma to induce dementia. One potential treatment is a "shunt operation" to bypass excess CSF from the ventricles to the peritoneal cavity, leading to the attenuation of dementia. After the shunt operation, marker levels began to increase within a week and then further increased by 2-2.5-fold at three, six, and twelve months post-operation, at which point symptoms had gradually attenuated. Notably, the marker levels were found to be correlated with each other in the post-operative period. In conclusion, the brain-derived major glycoprotein markers were highly correlated in the CSF of patients with different neurological diseases, and their correlations were maintained even after surgical intervention. These results suggest that brain-derived proteins could be biomarkers of CSF production.
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Demencia , Hidrocefalia , Enfermedades del Sistema Nervioso , Humanos , Encéfalo/metabolismo , Enfermedades del Sistema Nervioso/metabolismo , Glicoproteínas/metabolismo , Hidrocefalia/metabolismo , Demencia/metabolismo , Biomarcadores/metabolismoRESUMEN
BACKGROUND: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination. METHODS: We conducted an investigator-initiated phase 2 study of combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL. All patients had at least one of the following features: chromosome 17p deletion, mutated TP53, chromosome 11q deletion, unmutated IGHV, or an age of 65 years or older. Patients received ibrutinib monotherapy (420 mg once daily) for 3 cycles, followed by the addition of venetoclax (weekly dose escalation to 400 mg once daily). Combined therapy was administered for 24 cycles. Response assessments were performed according to International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. Minimal residual disease was assessed by means of multicolor flow cytometry in bone marrow (sensitivity, 10-4). RESULTS: A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time. After 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease. Responses were noted in older adults and across all high-risk subgroups. Three patients had laboratory evidence of tumor lysis syndrome. The adverse-event profile was similar to what has been reported with ibrutinib and venetoclax. CONCLUSIONS: In this study, combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL. (Funded by AbbVie and others; ClinicalTrials.gov number, NCT02756897.).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Sulfonamidas/administración & dosificación , Adenina/análogos & derivados , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Fibrilación Atrial/inducido químicamente , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Femenino , Humanos , Quimioterapia de Inducción , Leucemia Linfocítica Crónica de Células B/genética , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Mutación , Neoplasia Residual , Neutropenia/inducido químicamente , Piperidinas , Pirazoles/efectos adversos , Pirimidinas/efectos adversos , Inducción de Remisión , Sulfonamidas/efectos adversosRESUMEN
The promising activity of BET protein inhibitors (BETi's) is compromised by adaptive or innate resistance in acute myeloid leukemia (AML). Here, modeling of BETi-persister/resistance (BETi-P/R) in human postmyeloproliferative neoplasm (post-MPN) secondary AML (sAML) cells demonstrated accessible and active chromatin in specific superenhancers/enhancers, which was associated with increased levels of nuclear ß-catenin, TCF7L2, JMJD6, and c-Myc in BETi-P/R sAML cells. Following BETi treatment, c-Myc levels were rapidly restored in BETi-P/R sAML cells. CRISPR/Cas9-mediated knockout of TCF7L2 or JMJD6 reversed BETi-P/R, whereas ectopic overexpression conferred BETi-P/R in sAML cells, confirming the mechanistic role of the ß-catenin-TCF7L2-JMJD6-c-Myc axis in BETi resistance. Patient-derived, post-MPN, CD34+ sAML blasts exhibiting relative resistance to BETi, as compared with sensitive sAML blasts, displayed higher messenger RNA and protein expression of TCF7L2, JMJD6, and c-Myc and following BETi washout exhibited rapid restoration of c-Myc and JMJD6. CRISPR/Cas9 knockout of TCF7L2 and JMJD6 depleted their levels, inducing loss of viability of the sAML blasts. Disruption of colocalization of nuclear ß-catenin with TBL1 and TCF7L2 by the small-molecule inhibitor BC2059 combined with depletion of BRD4 by BET proteolysis-targeting chimera reduced c-Myc levels and exerted synergistic lethality in BETi-P/R sAML cells. This combination also reduced leukemia burden and improved survival of mice engrafted with BETi-P/R sAML cells or patient-derived AML blasts innately resistant to BETi. Therefore, multitargeted disruption of the ß-catenin-TCF7L2-JMJD6-c-Myc axis overcomes adaptive and innate BETi resistance, exhibiting preclinical efficacy against human post-MPN sAML cells.
Asunto(s)
Antineoplásicos/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/antagonistas & inhibidores , Antineoplásicos/química , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos , Humanos , Histona Demetilasas con Dominio de Jumonji/metabolismo , Leucemia Mieloide Aguda/metabolismo , Proteolisis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteína 2 Similar al Factor de Transcripción 7/metabolismo , Factores de Transcripción/metabolismo , beta Catenina/metabolismoRESUMEN
Tumour progression is an evolutionary process in which different clones evolve over time, leading to intra-tumour heterogeneity. Interactions between clones can affect tumour evolution and hence disease progression and treatment outcome. Intra-tumoural pairs of mutations that are overrepresented in a co-occurring or clonally exclusive fashion over a cohort of patient samples may be suggestive of a synergistic effect between the different clones carrying these mutations. We therefore developed a novel statistical testing framework, called GeneAccord, to identify such gene pairs that are altered in distinct subclones of the same tumour. We analysed our framework for calibration and power. By comparing its performance to baseline methods, we demonstrate that to control type I errors, it is essential to account for the evolutionary dependencies among clones. In applying GeneAccord to the single-cell sequencing of a cohort of 123 acute myeloid leukaemia patients, we find 1 clonally co-occurring and 8 clonally exclusive gene pairs. The clonally exclusive pairs mostly involve genes of the key signalling pathways.
Asunto(s)
Biología Computacional/métodos , Leucemia Mieloide Aguda , Algoritmos , Progresión de la Enfermedad , Humanos , Leucemia Mieloide Aguda/clasificación , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Modelos Estadísticos , Mutación/genética , Transducción de Señal/genéticaRESUMEN
Activating mutations in RAS have been reported in about 10-15% of patients with AML; previous studies have not identified a prognostic significance. However, RAS mutations have emerged as a potential resistance mechanism to treatment with inhibitors of FLT3, IDH, and BCL2. We aimed to determine the characteristics and outcomes of patients with RAS-mutated (RAS-mut) AML across therapy subsets of 1410 patients newly diagnosed (ND AML). RAS-mut was observed in 273 (20%) patients. Overall, patients with RAS-mut AML had an estimated 3-year survival rate of 38% vs. 28% in those with RAS wild type (RAS-wt), p = .01. Among patients with RAS-mut, favorable karyotype and concomitant NPM1 mutations were associated with a higher CR/CRi rate, OR 23.2 (95% CI: 2.7-192.7; p < .001) and OR 2.8 (95% CI: 1.1-6.9; p = .02), respectively, while secondary and treated secondary (ts)-AML were associated with low response rates, OR 0.34 (95% CI: 0.1-0.9; p = .04) and OR 0.22 (95% CI: 0.09-0.5; p = .001), respectively. Intensive chemotherapy was associated with high response rates OR 5.9 (95% CI: 2.9-12.2; p < .001). Better median OS was observed among those with favorable karyotype, HR 0.28 (95% CI: 0.1-0.6; p = .002), and those treated with intensive chemotherapy, HR 0.42 (95% CI: 0.2-0.6 p < .001). Conversely, ts- AML and co-occurrence of mutations in TP53 were associated with poor median OS; HR 2.3 (95% CI: 1.4-3.9; p = .001) and HR 1.7 (95% CI: 0.9-3.1; p = .06), respectively. The addition of venetoclax was associated with a non-significant improvement in CR/CRi and OS.
Asunto(s)
Leucemia Mieloide Aguda , Humanos , Tirosina Quinasa 3 Similar a fms/genética , Genes ras , Cariotipo , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Pronóstico , Proteínas ras/metabolismoRESUMEN
Fludarabine, cytarabine, GCSF (FLAG)-based induction/consolidation results in high remission rates in core binding factor (CBF) acute myelogenous leukemia. We treated 174 consecutive patients with newly diagnosed CBF-AML in a prospective clinical trial of FLAG-based induction/consolidation in combination with gemtuzumab ozogamicin (FLAG-GO; N = 65) or in combination with idarubicin (FLAG-IDA; N = 109). The 5 year RFS in the FLAG-GO cohort was significantly better than the FLAG-IDA cohort, 78% versus 59%, respectively (p-value = .02). In multivariate analysis for RFS, age (p = .0001), FLAG-GO regimen (p = .04), 4 log reduction in CBF-related fusion transcript by quantitative polymerase chain reaction (qPCR) in bone marrow samples at end of consolidation therapy (p = .03), and additional cytogenetic abnormalities (p = .03) were significant variables. Lower age (p = .0001) and 3 log or more transcript reduction at end of induction (p = .04) were significant variables predicting for better overall survival (OS), while there was strong trend for better OS with FLAG-GO (p = .06) regimen. FLAG-GO regimen was superior in optimal disease specific fusion transcript reduction at end of induction (p = .002), mid-consolidation (p < .01), and end of consolidation (p < .001) therapy. Induction/consolidation with FLAG-GO regimen results in better clinical outcomes in newly diagnosed patients with CBF-AML compared to FLAG-IDA and achieves deeper molecular clearance by qPCR assessment of the fusion transcripts.