Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 291
Filtrar
1.
Blood Cancer J ; 12(1): 5, 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35017466

RESUMO

Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.

2.
Sci Rep ; 12(1): 892, 2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35042966

RESUMO

The retinal pigment epithelium (RPE) is essential for the survival and function of retinal photoreceptor cells. RPE dysfunction causes various retinal diseases including age-related macular degeneration (AMD). Clinical studies on ES/iPS cell-derived RPE transplantation for RPE dysfunction-triggered diseases are currently underway. Quantification of the diseased RPE area is important to evaluate disease progression or the therapeutic effect of RPE transplantation. However, there are no standard protocols. To address this issue, we developed a 2-step software that enables objective and efficient quantification of RPE-disease area changes by analyzing the early-phase hyperfluorescent area in fluorescein angiography (FA) images. We extracted the Abnormal region. This extraction was based on deep learning-based discrimination. We scored the binarized extracted area using an automated program. Our program's performance for the same eye from the serial image captures was within 3.1 ± 7.8% error. In progressive AMD, the trend was consistent with human assessment, even when FA images from two different visits were compared. This method was applicable to quantifying RPE-disease area changes over time, evaluating iPSC-RPE transplantation images, and a disease other than AMD. Our program may contribute to the assessment of the clinical course of RPE-disease areas in routine clinics and reduce the workload of researchers.

3.
Exp Cell Res ; 412(1): 113006, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34979106

RESUMO

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.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34992253

RESUMO

The role of WT1 protein in hematopoiesis and leukemogenesisis incompletely elucidated. WT1 overexpression is common in acute myeloid leukemia (AML); however, WT1 mutations occur in only about 10% of cases, with increasing incidence in the setting of relapse. In this study, we investigated the clinical and molecular characteristics of WT1 mutations in NPM1-mutated AML, to enhance our understanding of the biology and potential therapeutic implications of WT1 mutations. Our study cohort included 67 patients with NPM1 mutated AML and a median follow-up of 13.7 months. WT1 mutations were identified in 7% (n = 5) of patients at the time of initial diagnosis. WT1 mutant clones were presumed to be present as co-dominant clones in 3/5 and in subclonal populations in 2/5 cases based on variant allelic frequency (VAF) when compared with NPM1 mutation VAF. All WT1 mutations became undetectable at time of MRD-negative (NPM1-wild type) remission. None of these patients experienced relapse at the time of last follow-up (median, 15 months; range, 4.5-20.2 months). A total of 15/67 (22%) patients relapsed; among these patient, four (27%) relapsed with WT1 mutant AML. Three of four patients had undergone allogeneic hematopoietic stem cell transplantation (HSCT). None of these patients had detectable WT1 mutations at the time of initial diagnosis. WT1 mutations were presumed clonal in two cases and subclonal in the other two cases, based on VAF. Our results indicate that WT1 mutations contribute to relapse in NPM1 mutated AML, especially in the setting of HSCT. These findings suggest that emerging WT1 mutations may serve as a conduit for relapse in NPM1-mutated AML, and that sequential molecular profiling to evaluate potential emergent WT1 mutations during surveillance and particularly at relapse likely has prognostic value in patients with NPM1 mutated AML.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34951129

RESUMO

TAS-114 is a dual deoxyuridine triphosphatase (dUTPase) and dihydropyrimidine dehydrogenase (DPD) inhibitor expected to widen the therapeutic index of capecitabine. Its maximum tolerated dose (MTD) was determined from a safety perspective in a combination study with capecitabine; however, its inhibitory effects on DPD activity were not assessed in the study. The dose justification to select its MTD as the recommended dose in terms of DPD inhibition has been required, but the autoinduction profile of TAS-114 made it difficult. To this end, an approach using a population pharmacokinetic (PPK)/pharmacodynamic (PD) model incorporating autoinduction was planned; however, the utility of this approach in the dose justification has not been reported. Thus, the aim of this study was to demonstrate the utility of a PPK/PD model incorporating autoinduction in the dose justification via a case study of TAS-114. Plasma concentrations of TAS-114 from 185 subjects and those of the endogenous DPD substrate uracil from 24 subjects were used. A two-compartment model with first-order absorption with lag time and an enzyme turnover model were selected for the pharmacokinetic (PK) model. Moreover, an indirect response model was selected for the PD model to capture the changes in plasma uracil concentrations. Model-based simulations provided the dose justification that DPD inhibition by TAS-114 reached a plateau level at the MTD, whereas exposures of TAS-114 increased dose dependently. Thus, the utility of a PPK/PD model incorporating autoinduction in the dose justification was demonstrated via this case study of TAS-114.

8.
PLoS Comput Biol ; 17(12): e1009036, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34910733

RESUMO

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.

9.
J Med Invest ; 68(3.4): 368-371, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34759160

RESUMO

Tazobactam / piperacillin (TAZ / PIPC) is an injectable combination drug consisting of a broad-spectrum penicillin and a ß-lactamase inhibitor. This antimicrobial has a wide spectrum of efficacy against both Gram-positive bacteria and anaerobes. Adverse events usually present as diarrhea or liver dysfunction ; agranulocytosis has not been reported in Japanese patients with puerperal disorders. However, we report a 32-year-old Japanese woman who received TAZ / PIPC to treat an intraperitoneal infection that developed after complications related to transvaginal delivery. Within 14 days of beginning TAZ / PIPC therapy, the patient developed agranulocytosis, indicated by a white blood cell count of 1900 cells / µL and a neutrophil count of 475 cells / µL. We discontinued TAZ / PIPC at this point and changed the antimicrobial to meropenem. Seven days later, her white blood cell count increased to 3700 cells / µL (neutrophil count : 1684 cells / µL), and the intraperitoneal infection resolved. Patients receiving TAZ / PIPC should be monitored periodically for agranulocytosis as well as for diarrhea and liver dysfunction. J. Med. Invest. 68 : 368-371, August, 2021.


Assuntos
Agranulocitose , Piperacilina , Adulto , Agranulocitose/induzido quimicamente , Agranulocitose/tratamento farmacológico , Antibacterianos/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Ácido Penicilânico/efeitos adversos , Piperacilina/efeitos adversos , Combinação Piperacilina e Tazobactam
10.
Blood ; 2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34601571

RESUMO

Majority of RUNX1 mutations in 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 to 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 to 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. HHT treatment repressed enhancers and their BRD4 occupancy, as well as was associated with reduced levels of c-Myc, c-Myb, MCL1 and Bcl-xL. Consistent with this, co-treatment with omacetaxine and venetoclax or BET inhibitor induced synergistic in vitro lethality in AML expressing mtRUNX1. Compared to each agent alone, co-treatment 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.

11.
Nat Commun ; 12(1): 6071, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663807

RESUMO

In contrast to the curative effect of allogenic stem cell transplantation in acute myeloid leukemia via T cell activity, only modest responses are achieved with checkpoint-blockade therapy, which might be explained by T cell phenotypes and T cell receptor (TCR) repertoires. Here, we show by paired single-cell RNA analysis and TCR repertoire profiling of bone marrow cells in relapsed/refractory acute myeloid leukemia patients pre/post azacytidine+nivolumab treatment that the disease-related T cell subsets are highly heterogeneous, and their abundance changes following PD-1 blockade-based treatment. TCR repertoires expand and primarily emerge from CD8+ cells in patients responding to treatment or having a stable disease, while TCR repertoires contract in therapy-resistant patients. Trajectory analysis reveals a continuum of CD8+ T cell phenotypes, characterized by differential expression of granzyme B and a bone marrow-residing memory CD8+ T cell subset, in which a population with stem-like properties expressing granzyme K is enriched in responders. Chromosome 7/7q loss, on the other hand, is a cancer-intrinsic genomic marker of PD-1 blockade resistance in AML. In summary, our study reveals that adaptive T cell plasticity and genomic alterations determine responses to PD-1 blockade in acute myeloid leukemia.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Azacitidina/uso terapêutico , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Resistencia a Medicamentos Antineoplásicos/genética , Granzimas/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Receptores de Antígenos de Linfócitos T/genética , Análise de Célula Única , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma/efeitos dos fármacos
12.
Blood Adv ; 5(23): 5415-5419, 2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34525185

RESUMO

Acute lymphoblastic leukemia (ALL) with t(4;11)(q21;q23)-KMT2A-AFF1 is associated with a poor prognosis. The impact of KMT2A rearrangements other than t(4;11) is uncertain, and the benefit of allogeneic stem cell transplantation (HSCT) is unclear. We reviewed adult patients with ALL treated at our institution from 1984 to 2019 and identified 50 out of 1102 (5%) with KMT2A rearrangement, including 42 (84%) with t(4;11)/KMT2A-AFF1 and 8 (16%) with other gene partners. The median age was 45 years (range, 18-78 years); median white blood cell count was 109.0 3 109/L (range, 0.5-1573.0). The complete remission (CR) rate was 88%, and the rate of measurable residual disease negativity by flow cytometry at CR was 41% (76% overall during follow-up). At the last follow-up, 14 patients were alive. The 5-year overall survival (OS) rate was 18% (95% confidence interval [CI], 9% to 35%), with no difference between t(4;11) and other KMT2A rearrangements (P 5 .87). In a 4-month landmark analysis, the 5-year OS rate was 32% (95% CI, 14% to 70%) in patients who underwent HSCT vs 11% (95% CI, 3-39) in others (P 5 .10). Our study confirms the poor prognosis of ALL with any KMT2A rearrangement and the role of HSCT in these patients.

14.
Am J Hematol ; 96(11): 1420-1428, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34351647

RESUMO

TP53 mutations in acute myeloid leukemia (AML) are associated with resistance to standard treatments and dismal outcomes. The incidence and prognostic impact of the emergence of newly detectable TP53 mutations over the course of AML therapy has not been well described. We retrospectively analyzed 200 patients with newly diagnosed TP53 wild type AML who relapsed after or were refractory to frontline therapy. Twenty-nine patients (15%) developed a newly detectable TP53 mutation in the context of relapsed/refractory disease. The median variant allelic frequency (VAF) was 15% (range, 1.1%-95.6%). TP53 mutations were more common after intensive therapy versus lower-intensity therapy (23% vs. 10%, respectively; p = 0.02) and in patients who had undergone hematopoietic stem cell transplant versus those who had not (36% vs. 12%, respectively; p = 0.005). Lower TP53 VAF was associated with an increased likelihood of complete remission (CR) or CR with incomplete hematologic recovery (CRi) compared to higher TP53 VAF (CR/CRi rate of 41% for VAF < 20% vs. 13% for VAF ≥ 20%, respectively). The median overall survival (OS) after acquisition of TP53 mutation was 4.6 months, with a 1-year OS rate of 19%. TP53 VAF at relapse was significantly associated with OS; the median OS of patients with TP53 VAF ≥ 20% was 3.5 months versus 6.1 months for those with TP53 VAF < 20% (p < 0.05). In summary, new TP53 mutations may be acquired throughout the course of AML therapy. Sequential monitoring for TP53 mutations is likely to be increasingly relevant in the era of emerging TP53-targeting therapies for AML.


Assuntos
Leucemia Mieloide Aguda/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Gerenciamento Clínico , Frequência do Gene , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/terapia , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , Adulto Jovem
15.
Oecologia ; 197(1): 259-269, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34392417

RESUMO

As per the abundant-center hypothesis, the cold- and warm-edges of the latitudinal and elevational distributions of vegetation are the result of physiological limitations caused by abiotic stress. The stand-level productivity per leaf mass of plants is an integrated physiological measure of whole-plant carbon gain. The abundant-center hypothesis specifically predicts that the productivity per leaf mass decreases at cold-edges and warm-edges. In the Japanese archipelago, the dominant functional types of trees change from evergreen hardwoods in the south to deciduous hardwoods and evergreen conifers in the north, forming latitudinal ecotones. This study tested the abundant-center hypothesis by analyzing the productivity per leaf mass of each functional type along a gradient of mean annual temperature (MAT), using forest inventory data. Although productivity per leaf mass was variable along the MAT, it neither increased nor decreased with MAT for each functional tree type. The productivity per leaf mass was also noted to not decrease at the cold-edges for evergreen and deciduous hardwoods or at the warm-edges for deciduous hardwoods and evergreen conifers. Productivity per leaf mass was not positively correlated with abundance. Thus, this study did not support the abundant-center hypothesis. Instead, physiological or ecological limitations, particularly at the seedling and sapling stages, may be the important process affecting the distribution edges of these three functional types.


Assuntos
Florestas , Árvores , Clima , Japão , Folhas de Planta
16.
Sci Total Environ ; 799: 149368, 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34352461

RESUMO

Soil fungi play an important role in promoting nutrient cycling and maintaining ecosystem stability. Yet, there has been little understanding of how fungal co-occurrence networks differ along elevational climate gradients, a topic of interest to both macroecology and climate change studies. Based on high-throughput sequencing technology, we investigated the trend in co-occurrence network structure of soil fungal communities at 11 elevation levels along a 2300 m elevation gradient on Mt. Norikura, Japan, and identified the keystone taxa in the network, hypothesizing a progressive decline in network connectivity with elevation due to decreased plant diversity and enhanced environmental stress caused by changes in climate and soil characteristics. Our results demonstrated that network-level topological features such as network size, average degree, clustering coefficient, and modularity decreased significantly with increasing elevation, indicating that the fungal OTUs at low elevation were more closely associated and the network structure was more compact at low elevations. This conclusion was verified by the negative correlation between positive cohesion, negative cohesion and elevation. Moreover, the negative/positive cohesion ratio reached its peak value in mid-elevations with moderate environmental stress, indicating that the fungal community structure in mid-elevations was more stable than that at other elevations. We also found that the keystone taxa were more abundant at lower elevations. Furthermore, statistical analysis revealed that against a background of uniform geology, climate may play a dominant role in determining the properties and intensity of soil fungal networks, and significantly affect the abundance distribution of keystone taxa. These findings enhance understanding of the pattern and mechanism of the fungal community co-occurrence network along elevation, as well as the responses of microorganisms to climate change on a vertical scale in montane ecosystems. IMPORTANCE: Exploration of the elevational distribution of microbial networks and their driving factors and mechanisms may provide opportunities for predicting potential impacts of environmental changes, on ecosystem functions and biogeographic patterns at a broad scale. Although many studies have explored patterns of fungal community diversity and composition along various environmental gradients, it is unclear how the topological structure of co-occurrence networks shifts along elevational temperature gradients. In this study, we found that the connectivity of the fungal community decreased with increasing elevation and that climate was the dominant factor regulating co-occurrence patterns, apparently acting indirectly through soil characteristics. Our results also suggest that higher elevations on mountains have fewer keystone taxa than low elevations. These patterns may be related to the decrease of plant diversity and the increase of environmental stress along elevation gradients.


Assuntos
Ecossistema , Micobioma , Biodiversidade , Fungos , Japão , Solo , Microbiologia do Solo
17.
Fukushima J Med Sci ; 67(2): 64-70, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34373399

RESUMO

Spontaneous intracranial hypotension (SIH) is caused by cerebrospinal fluid (CSF) leakage. Patients with SIH experience postural headaches, nausea, etc., due to CSF hypovolemia. Imaging studies and clinical examinations, such as radioisotope (RI) scintigraphy, are useful for diagnosing SIH. However, 20-30% of patients do not show typical morphology and clinical test results. We previously reported that CSF contains transferrin (Tf) isoforms:"brain-type" Tf derived from the choroid plexus and "serum-type" Tf derived from blood. We showed that both isoforms increased in the CSF of patients with SIH by Western blotting. In the present study, we demonstrate that conventional ELISA for quantifying total Tf is useful for diagnosing SIH more accurately than Western blotting. In addition, SIH with chronic subdural hematoma (CSDH) was also accurately diagnosed. Total Tf in the CSF can serve as a useful biomarker for diagnosing SIH with or without CSDH.


Assuntos
Hipotensão Intracraniana , Biomarcadores , Encéfalo , Vazamento de Líquido Cefalorraquidiano/diagnóstico , Humanos , Hipotensão Intracraniana/diagnóstico , Transferrina
18.
Mediterr J Hematol Infect Dis ; 13(1): e2021044, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276913

RESUMO

Ibrutinib is a well-tolerated and effective therapy used for the treatment of chronic lymphocytic leukemia (CLL). However, its use has been associated with cardiovascular events such as atrial fibrillation (Afib), hypertension, and ventricular arrhythmias. Cardiac arrhythmias represent a significant cause of morbidity and mortality. Implanted loop recorders have been integrated into our clinical practice and have been considered a useful tool in guiding the management of patients with cardiac arrhythmias. We report a case that describes our experience on a patient diagnosed with CLL treated with ibrutinib.

19.
Cancer ; 127(20): 3772-3781, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34255353

RESUMO

BACKGROUND: TP53 mutation (TP53mut ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53mut confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53mut AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.gov identifier NCT03404193). METHODS: Patients with newly diagnosed AML received decitabine 20 mg/m2 for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53mut was identified in bone marrow samples using next-generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines. RESULTS: Among 118 patients (median age, 72 years; age range, 49-89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53mut AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%-65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53mut AML compared with those who had wild-type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60-day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53mut versus wild-type TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Outcomes with DEC10-VEN in patients with TP53mut AML were comparable to historical results with 10-day decitabine alone. CONCLUSIONS: Patients with TP53mut AML have lower response rates and shorter survival with DEC10-VEN.

20.
Sci Adv ; 7(30)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34290089

RESUMO

Metabolic dysregulation underlies malignant phenotypes attributed to cancer stem cells, such as unlimited proliferation and differentiation blockade. Here, we demonstrate that NAD+ metabolism enables acute myeloid leukemia (AML) to evade apoptosis, another hallmark of cancer stem cells. We integrated whole-genome CRISPR screening and pan-cancer genetic dependency mapping to identify NAMPT and NMNAT1 as AML dependencies governing NAD+ biosynthesis. While both NAMPT and NMNAT1 were required for AML, the presence of NAD+ precursors bypassed the dependence of AML on NAMPT but not NMNAT1, pointing to NMNAT1 as a gatekeeper of NAD+ biosynthesis. Deletion of NMNAT1 reduced nuclear NAD+, activated p53, and increased venetoclax sensitivity. Conversely, increased NAD+ biosynthesis promoted venetoclax resistance. Unlike leukemia stem cells (LSCs) in both murine and human AML xenograft models, NMNAT1 was dispensable for hematopoietic stem cells and hematopoiesis. Our findings identify NMNAT1 as a previously unidentified therapeutic target that maintains NAD+ for AML progression and chemoresistance.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...