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In recent years, one of the most promising advances in the treatment of acute myeloid leukemia (AML) is the combination of a hypomethylating agent (HMA) with the BCL2 inhibitor venetoclax (VEN). To better understand the key factors associated with the response of VEN plus HMA, 212 consecutive AML patients were retrospectively recruited to establish and validate a scoring system for predicting the primary resistance to VEN-based induced therapy. All AML patients were divided randomly into a training set (n = 155) and a validation set (n = 57). Factors were selected using a multivariate logistic regression model, including FAB-M5, myelodysplastic syndrome-secondary acute myeloid leukemia (MDS-sAML), RUNX1-RUNX1T1 and FLT3-ITD mutation (FLT3-ITDm). A nomogram was then constructed including all these four predictors. The nomogram both presented a good performance of discrimination and calibration, with a C-index of 0.770 and 0.733 in the training and validation set. Decision curve analysis also indicated that the nomogram was feasible to make beneficial decisions. Eventually a total scoring system of 8 points was developed, which was divided into three risk groups: low-risk (score 0-2), medium-risk (score 3-4), and high-risk (score 5-8). There was a significant difference in the nonremission (NR) rate of these three risk groups (22.8% vs. 60.0% vs. 77.8%, p < 0.001). After adjustment of the other variables, patients in medium- or high-risk groups also presented a worse event-free survival (EFS) than that in the low-risk group (hazard ratio [HR] = 1.62, p = 0.03). In conclusion, we highlighted the response determinants of AML patients receiving a combination therapy of VEN plus HMAs. The scoring system can be used to predict the resistance of VEN, providing better guidance for clinical treatment.
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Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Estudios Retrospectivos , Antineoplásicos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Circulating tumor cells (CTCs) indicate the diagnosis and prognosis of cancer patients, together with benefiting individual treatment and anticancer drug development. However, their large-scale application in general population still requires systematically multifaceted modifications for currently proprietary new technologies based on filtration. We primitively utilized a cell size-based platform to evaluate the recovery efficiency of spiked abnormal cell lines and analyzed circulating abnormal cells (CACs). To dissect the subpopulations of CACs, we conducted immunofluorescent (IF) staining with a combination of unique biomarkers of CTCs and circulating endothelial cells (CECs). Furthermore, we improved the CTC screening system by assessing the feasibility of transferring CTCs for automatic IF analysis, together with simulating and optimizing the circumstances for long-term CTC storage and transportation. We detected CACs in 15 HD candidates with CTC characteristics such as abnormally large cytomorphology, high nuclear-cytoplasmic ratio, and positive for panCK or VIM staining. Thereafter, we improved accuracy of the platform by distinguishing CTCs from CECs, which satisfied the elementary requirement for small-scale CTC screening in HD candidates. Finally, large-scale CTC screening in general population was available after multifaceted modifications including automatic analysis by transferring CTCs on slides, choosing the appropriate blood-collecting tube, optimizing the conditions for long-term CTC storage and transportation, and evaluating the potential effect on the CTC phenotype. Hence, we systematically modified the scope of technique parameters, improved the accuracy of early cancer detection, and made it realizable for large-scale CTC or CEC screening in general population.
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Células Endoteliales , Neoplasias , Células Neoplásicas Circulantes , Adulto , Anciano , Biomarcadores de Tumor , Células Endoteliales/citología , Células Endoteliales/ultraestructura , Femenino , Células HT29 , Humanos , Masculino , Tamizaje Masivo , Células Madre Mesenquimatosas , Persona de Mediana Edad , Neoplasias/diagnóstico por imagen , Neoplasias/patología , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/ultraestructura , Adulto JovenRESUMEN
BACKGROUND AIMS: Imatinib (IM), a tyrosine kinase inhibitor targeting the BCR-ABL oncoprotein, remains a major therapeutic strategy for patients with chronic myelogenous leukemia (CML). However, IM resistance is still a challenge in the treatment of CML. Recently, it was reported that exosomes (Exo) were involved in drug resistance. Therefore, the present study investigated whether Exo secreted by human umbilical cord mesenchymal stromal cells (hUC-MSC-Exo) affected the sensitivity of K562 cells to IM. METHODS: hUC-MSC-Exo were isolated and identified. K562 cells were then treated or not with IM (1 µmol/L) in combination with hUC-MSC-Exo (50 µg/mL). Cell viability and apoptosis were determined by cell counting kit 8 (CCK-8) and annexin V/propidium iodide (PI) double staining, respectively. Apoptotic proteins, caspase and their cleaved forms were detected by Western blot. RESULTS: It was shown that hUC-MSC-Exo alone had no effect on cell viability and apoptosis of K562 cells. However, hUC-MSC-Exo promoted IM-induced cell viability inhibition and apoptosis. Moreover, hUC-MSC-Exo enhanced the increased Bax expression and the decreased Bcl-2 expression that were induced by IM. Compared with IM alone, caspase-9 and caspase-3 were further activated by combination of hUC-MSC-Exo with IM. Finally, the effects of hUC-MSC-Exo on K562 cells could be reversed by pretreatment of K562 cells with caspase inhibitor Z-VAD-FMK (30 µmol/L) DISCUSSION: These results indicate that hUC-MSC-Exo enhanced the sensitivity of K562 cells to IM via activation of caspase signaling pathway. Therefore, combining IM with hUC-MSC-Exo could be a promising approach to improve the efficacy of CML treatment.
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Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Exosomas/metabolismo , Mesilato de Imatinib/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Células Madre Mesenquimatosas/metabolismo , Transducción de Señal , Supervivencia Celular/efectos de los fármacos , Exosomas/efectos de los fármacos , Humanos , Células K562 , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Transducción de Señal/efectos de los fármacosAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Decitabina/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Adulto , Femenino , Humanos , Mutación/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: The Notch signaling pathway is implicated in a broad range of developmental processes, including cell fate decisions. This study was designed to determine the role of Notch signaling in adipogenic differentiation of human bone marrow derived MSCs (BM-MSCs). METHODS: The Notch signaling was inhibited by the γ-secretase inhibitor N-[N-(3,5-difluor- ophenacetyl-L-alanyl)]-S-phenylglycine t-butylester (DAPT). The markers involving adipogenic differentiation of MSCs, the relative pathway PTEN-PI3K/Akt/mTOR and autophagy activation were then analyzed. Furthermore, the autophagy inhibitor chloroquine (CQ) and 3-methyladenine (3-MA) were used to study the role of autophagy in the DAPT-induced the adipogenic differentiation of MSCs. RESULTS: We first confirmed the down -regulation of Notch gene expression during MSCs adipocyte differentiation, and showed that the inhibition of Notch signaling significantly enhanced adipogenic differentiation of MSCs. Furthermore, Notch inhibitor DAPT induced early autophagy by acting on PTEN-PI3K/Akt/mTOR pathway. The autophagy inhibitor CQ and 3-MA dramatically abolished the effects of DAPT-induced autophagy and adipogenic differentiation of MSCs. CONCLUSION: Our results indicate that inhibition of Notch signaling could promote MSCs adipogenesis mediated by autophagy involving PTEN-PI3K/Akt/mTOR pathway. Notch signaling could be a novel target for regulating the adipogenic differentiation of MSCs.
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Tejido Adiposo/citología , Autofagia , Diferenciación Celular , Dipéptidos/farmacología , Células Madre Mesenquimatosas/citología , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores Notch/antagonistas & inhibidores , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Células Cultivadas , Humanos , Receptores Notch/metabolismoRESUMEN
Lipocalin 2 (LCN2), a multifunctional secretory protein known as neutrophil gelatinase-associated lipocalin (NGAL), is expressed in a variety of cancers. However, little is known about the biological functions of NGAL in the development of lung adenocarcinoma. In the present study, we primarily found that NGAL expression was up-regulated in human lung adenocarcinoma tissues. Additionally, depletion of NGAL expression decreased the ability of cell proliferation and induced cell apoptosis. Furthermore, with the addition of N-acetylcysteine, a scavenger of reactive oxygen species (ROS), it was found that NGAL depletion was sufficient to cause apoptosis of lung adenocarcinoma cells by generating ROS through the inhibition of the nuclear factor E2-related factor 2/heme oxygenase-1 anti-oxidant pathway. Finally, the effect of NGAL down-regulation on the growth of human lung adenocarcinoma was determined in BALB/c nude mice. These findings demonstrate that NGAL may be a potential therapy target for patients with lung adenocarcinoma.
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Proteínas de Fase Aguda/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Hemo-Oxigenasa 1/metabolismo , Lipocalinas/metabolismo , Neoplasias Pulmonares/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Regulación hacia Abajo , Femenino , Humanos , Lipocalina 2 , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Transducción de SeñalRESUMEN
AIM: Recent studies have demonstrated that Notch signalling pathway is an important mediator of cardiac repair and regeneration after myocardial infarction. However, the mechanism by which Notch signalling pathway is mediating cardioprotection after ischaemic postconditioning (IPost) is still not understood thoroughly. The aim of the present study was to investigate the mechanism by which Notch signalling pathway mediated the cardioprotection effect after IPost. METHODS: Rat heart-derived H9c2 cells were randomly divided into six groups as follows: Control group, hypoxia/reoxygenation group (H/R), H/R+N1ICD group, H-post group, H-post+Notch-1miRNA group, and Mock group. We used pcDNA3.1-Myc-His plasmid and RNA interference (RNAi) to activate/inhibit the expression of Notch-1 in H9c2 cell lines. The Bcl-2, Bax genes and proteins were assessed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and Western blot analysis. The effects of Notch 1 signalling on cell survival, proliferation and apoptosis were detected by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and flow cytometry analysis, respectively. Furthermore, Notch 1 signalling induced the disruption of mitochondrial membrane potential, thus leading to the activation of caspase-9/-3 measured using the colorimetric activity assay. RESULTS: We found Notch 1 signalling reduced cardiomyocyte apoptosis in IPost through regulating the expression of Bcl-2, Bax and activation of caspase-9 and -3. We found that after transfected with pcDNA3.1-Myc-His plasmid, activation of the Notch 1 gene effectively promoted cell proliferation and inhibited apoptosis. The Notch 1 upregulation was accompanied by an upregulation of Bcl-2 and a downregulation of Bax. In addition, a paralled increase in caspase-9/-3 activities was observed. These effects were blunted by transfected with Notch-1 miRNA in the H9c2 cells. CONCLUSION: Notch 1 signalling has a cardioprotection effect, which may result from cardiomyocyte apoptosis, by means of regulating the expression of cell apoptosis inhibiting proteins Bcl-2, Bax and the activation of caspase-9 and -3.
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Apoptosis/fisiología , Precondicionamiento Isquémico Miocárdico , Miocitos Cardíacos/metabolismo , Receptor Notch1/metabolismo , Transducción de Señal/fisiología , Animales , Proteínas Reguladoras de la Apoptosis/biosíntesis , Proteínas Reguladoras de la Apoptosis/genética , Línea Celular , Regulación de la Expresión Génica/fisiología , Miocitos Cardíacos/citología , Ratas , Receptor Notch1/genéticaRESUMEN
Adverse-risk acute myeloid leukemia (AML) has a dismal prognosis. We aimed to investigate the activity and tolerability of venetoclax combined with homoharringtonine (HHT) plus cytarabine (VHA) regimen for de novo adverse-risk AML. Thirteen de novo AML patients with adverse-risk factors were treated with venetoclax (100 mg day 1, 200 mg day 2, 400 mg days 3-21), HHT (1 mg/m2 days 1-5) and cytarabine (100 mg/m2 days 1-5) (VHA regimen). Complete remission (CR) was achieved in 11/13 patient (84.6%), all of CR responders were measurable residual disease (MRD) negative detected by multi-parameter flow cytometry (MFC). Grade 3-4 neutropenia, anaemia, and thrombocytopenia occurred in most patients. Grade 3-4 non haematological adverse events (AEs) included febrile neutropenia (4/13, 30.8%). With a median follow-up of 10 months (range 4-19), median overall survival and event-free survival were not reached. VHA may be a promising and well-tolerated regimen in de novo adverse-risk AML.
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Acute myeloid leukemia (AML) is a deadly disease and the most common leukemia in adult with clonal heterogeneity and abnormity in myeloid lineages, which has been recognized with high morbidity and mortality attributes to the recurrence and resistance to chemotherapy. Numerous literatures have indicated the encouraging progress in allogeneic hematopoietic stem cell transplantation (allo-HSCT) and chimeric antigen receptor-transduced T (CAR-T) cells. However, the outcomes of recurrent and refractory AML (r/rAML) patients with current strategies are still unsatisfactory, which largely due to the matching restriction as well as adverse reactions, including graft-versus-host disease (GvHD), neurotoxicity and cytokine release syndrome (CRS). State-of-the-art literatures have indicated CAR-transduced NK (CAR-NK) cells for the management of diverse hematologic malignancies including AML, which are recognized as novel weapons for reinforcing the specificity and cytotoxicity of autogenous and allogeneic "off-the-shelf" NK cells dispense with prior sensitization. Therefore, in this review, we mainly focus on the latest updates of alternative cell sources, therapeutic targets, CAR-modification and delivery strategies, standardization and productization, together with prospective and challenges of CAR-NK cell-based cytotherapy, which will collectively benefit the further development of novel treatment paradigms for combating AML via both CAR-dependent and NK cell receptor-dependent signaling cascades in future.
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Variant acute promyelocytic leukemia (APL) showed quite different aspects, and the current treatments remained challenged at present. Venetoclax, a selective inhibitor of B-cell lymphoma 2 (BCL-2), is a small molecule that has been studied in several hematologic malignancies as both monotherapy and in combination with other agents. However, there is little of its use in the treatment of APL or variant APL. In this report, we identified THRAP3 as novel RARA fusion in resembling APL, which was resistant to all-trans retinoic acid (ATRA) combined arsenic trioxide (ATO) chemotherapy. Then, the patient was salvaged by low-dose venetoclax and decitabine. The treatment in this case demonstrates the potential ability of venetoclax in variant APL, thus providing a new treatment option for all kinds of APL.
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Natural killer (NK) cells are lymphocytes and play a pivotal role in innate and adaptive immune responses against infections and malignancies. Longitudinal studies have indicated the feasibility of perinatal blood for large-scale NK cell generation, yet the systematic and detailed comparations of the signatures of resident and expanded NK cells (rNKs, eNKs) are largely obscure. Herein, we harvested rNKs from umbilical cord blood (rUC-NKs) and placental blood (rP-NKs) as well as the corresponding eNKs (eUC-NKs, eP-NKs). Furthermore, the biological properties and transcriptomic signatures including cellular subpopulations, cytotoxicity, gene expression profiling, genetic characteristics, signaling pathways and gene set-related biological process were investigated. The enriched rNKs and eNKs exhibited diversity in biomarker expression pattern, and eNKs with higher percentages of NKG2D+, NKG2A+, NKp44+ and NKp46+ subsets. rNKs or eNKs with different origins showed more similarities in transcriptomic signatures than those with the same origin. Our data revealed multifaceted similarities and differences of the indicated rNKs and pNKs both at the cellular and molecular levels. Our findings provide new references for further dissecting the efficacy and molecular mechanisms of rNKs and eNKs, which will collectively benefit the fundamental and translational studies of NK cell-based immunotherapy.
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BACKGROUND: State-of-the-art advances have indicated the pivotal characteristics of bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) in hematopoietic microenvironment as well as coordinate contribution to hematological malignancies. However, the panoramic view and detailed dissection of BM-MSCs in patients with acute myeloid leukemia (AML-MSCs) remain obscure. METHODS: For the purpose, we isolated and identified AML-MSCs together with healthy donor-derived HD-MSCs from the bone marrow mononuclear cells (BM-MNCs) by using the standard density gradient centrifugation based on clinical diagnosis and cellular phenotypic analysis. Subsequently, we systematically compared the potential similarities and discrepancy both at the cellular and molecular levels via flow cytometry, multilineage differentiation, chromosome karyotyping, cytokine quantification, and transcriptome sequencing and bioinformatic analysis including single-nucleotide polymorphism (SNP), gene ontology (GO), HeatMap, principal component analysis (PCA), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). RESULTS: On the one hand, AML-MSCs exhibited undistinguishable signatures in cytomorphology, surface biomarker expression pattern, stemness, chromosome karyotype, and chondrogenesis as HD-MSCs, whereas with impaired adipogenesis, enhanced osteogenesis, and variations in cytokine expression pattern. On the other hand, with the aid of genomic and bioinformatic analyses, we verified that AML-MSCs displayed multidimensional discrepancy with HD-MSCs both in genome-wide gene expression profiling and genetic variation spectrum. Simultaneously, the deficiency of cellular vitality including proliferation and apoptosis in AML-MSCs was largely rescued by JAK-STAT signaling inhibition. CONCLUSIONS: Overall, our findings elucidated that AML-MSCs manifested multifaceted alterations in biological signatures and molecular genetics, and in particular, the deficiency of cellular vitality ascribed to over-activation of JAK-STAT signal, which collectively provided systematic and overwhelming new evidence for decoding the pathogenesis of AML and exploring therapeutic strategies in future.
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Leucemia Mieloide Aguda , Células Madre Mesenquimatosas , Médula Ósea , Células de la Médula Ósea , Proliferación Celular , Humanos , Leucemia Mieloide Aguda/genética , Transcriptoma , Microambiente TumoralRESUMEN
OBJECTIVE: To investigate the correlation between pretransplant serum ferritin (SF) level and prolonged or prolonged isolated thrombocytopenia (PT) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: The clinical data of 35 patients with PT after allo-HSCT were retrospectively analyzed, and 35 patients were matched according to age and sex as a controls from 424 allo-HSCT patients with normal platelet count. The serum ferritin level before the transplantation was analyzed. The potential risk factors were analyzed by chi-square test and Fisher's exact test as well as univariate and multivariate logistic regression. The survival curve was estimated by the Kaplan-Meier model to explore its clinical significance. In addition, ROC curve was used to verify the predictive power of SF. RESULTS: Compared with control group, the SF level in the PT group before transplantation significantly increased (P=0.001). Multivariate analysis results showed that SF level before transplantation was a risk factor for prolonged thrombocytopenia after HSCT, and patients with SF≥1000 ng / ml showed a higher risk of death (P=0.014). ROC curve showed that SF level could be used as a predictor of prolonged thrombocytopenia after allo-HSCT. CONCLUSION: The SF level before allo-HSCT relates with occurrence and prognosis of PT in patients after allo-HSCT. Detection of SF level can provide guidance for the intervention of prolonged thrombocytopenia after HSCT.
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Trasplante de Células Madre Hematopoyéticas , Trombocitopenia , Ferritinas , Humanos , Estudios Retrospectivos , Trasplante HomólogoRESUMEN
Reduced megakaryocyte (MK) apoptosis and insufficient platelet production play important roles in the pathogenesis of immune thrombocytopenia (ITP). The contribution of plasma-derived exosomes to the decreased platelet count in ITP has not been entirely understood. Here, we found the percentage of apoptotic MKs in patients with ITP was significantly lower than those in healthy volunteers. In the presence of ITP plasma-derived exosomes (ITP-Exo), the apoptosis of MKs was reduced during the process of MK differentiation in vitro, which contributed to the reduced platelet production by Bcl-xL/caspase signaling. Furthermore, in vivo study demonstrated that ITP-Exo administration led to significantly delayed platelet recovery in mice after 3.5 Gy of irradiation. All these findings indicated that ITP-Exo, as a regulator of platelet production, impaired MK apoptosis and platelet production through Bcl-xL/caspase signaling, unveiling new mechanisms for reduced platelet count in ITP.
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Apoptosis , Plaquetas/metabolismo , Exosomas/metabolismo , Megacariocitos/metabolismo , Púrpura Trombocitopénica Idiopática/sangre , Trombopoyesis , Adolescente , Adulto , Anciano , Animales , Apoptosis/efectos de la radiación , Plaquetas/patología , Plaquetas/efectos de la radiación , Estudios de Casos y Controles , Caspasas/sangre , Células Cultivadas , Exosomas/trasplante , Femenino , Rayos gamma , Humanos , Masculino , Megacariocitos/patología , Ratones Endogámicos BALB C , Persona de Mediana Edad , Recuento de Plaquetas , Púrpura Trombocitopénica Idiopática/diagnóstico , Trombopoyesis/efectos de la radiación , Adulto Joven , Proteína bcl-X/sangreRESUMEN
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for acute myeloid leukemia (AML). However, most patients experience relapse after allo-HSCT, with a poor prognosis, and treatment options are limited. The lack of an ideal targetable antigen is a major obstacle for treating patients with relapsed AML. CD38 is known to be expressed on most AML and myeloma cells, and its lack of expression on hematopoietic stem cells (HSCs) renders it a potential therapeutic target for relapsed AML. To investigate the clinical therapeutic efficacy and safety of CD38-targeted chimeric antigen receptor T (CAR-T-38) cells, we enrolled 6 AML patients who experienced relapse post-allo-HSCT (clinicaltrials.gov: NCT04351022). Prior to CAR-T-38 treatment, the blasts in the bone marrow of these patients exhibited a median of 95% (92-99%) CD38 positivity. Four weeks after the initial infusion of CAR-T-38 cells, four of six (66.7%) patients achieved complete remission (CR) or CR with incomplete count recovery (CRi); the median CR or CRi time was 191 (range 117-261) days. The cumulative relapse rate at 6 months was 50%. The median overall survival (OS) and leukemia-free survival (LFS) times were 7.9 and 6.4 months, respectively. One case relapsed 117 days after the first CAR-T-38 cell infusion, with remission achieved after the second CAR-T-38 cell infusion. All six patients experienced clinically manageable side effects. In addition, multiparameter flow cytometry (FCM) revealed that CAR-T-38 cells eliminated CD38 positive blasts without off-target effects on monocytes and lymphocytes. Although this prospective study has a limited number of cases and a relatively short follow-up time, our preliminary data highlight the clinical utility and safety of CAR-T-38 cell therapy in treating relapsed AML post-allo-HSCT.
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ADP-Ribosil Ciclasa 1/metabolismo , Trasplante de Células Madre Hematopoyéticas/métodos , Inmunoterapia/métodos , Leucemia Mieloide Aguda/tratamiento farmacológico , Receptores Quiméricos de Antígenos/metabolismo , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/métodos , HumanosRESUMEN
Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) and T-lymphoid/myeloid mixed phenotype acute leukemia (T/M-MPAL) are closely related entities and remain a therapeutic challenge. In this study, we characterized the clinical features of 43 ETP-ALL and 41 T/M-MPAL patients and compared clinical outcomes and safety between cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CAG)-like regimens in 34 patients and conventional ALL regimens in 50 patients. In our series, ETP-ALL and T/M-MPAL showed similar biological characteristics, immunophenotypes, genomic alterations, and outcomes. The complete remission (CR) rate and minimal residual disease (MRD)-negative CR rate of CAG-like regimens were significantly higher compared with conventional ALL regimens (CAG-like: 80.0% and 59.7%, respectively; P = .039; ALL: 51.4% and 31.3%, respectively; P = .048). Overall, 90.0% of cases (18/20) achieved CR using combined decitabine and CAG-like regimens. Additionally, CAG-like regimens had lower rates of grade 3 or 4 infection (18.8% vs. 38.2%; P = .059) and grade 1 or 2 hepatotoxicity (37.5% vs. 60.0%; P = .043) than conventional ALL regimens. The 38 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the first CR (CR1) had better overall survival (OS) and leukemia-free survival (LFS) than the 11 patients who underwent allo-HSCT in the second CR (CR2) or in no remission (median OS not reached vs. 7.6 months, P = .0004; median LFS not reached vs. 11.6 months, P = .0008). There was a significant difference in 3-year OS (95.7% vs. 52.5%; P = .0039) and LFS (95.8% vs. 43.5%; P = .0003) after allo-HSCT between pre-transplant MRD-negative and MRD-positive patients. The median OS for patients without allo-HSCT was 32.1 months in the CAG-like group compared with 12.1 months in the non-CAG-like group (P = .019). These findings suggest that ETP-ALL and T/M-MPAL possess overlapping characteristics and CAG-like regimens improve their clinical outcomes.
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Trasplante de Células Madre Hematopoyéticas , Células Precursoras de Linfocitos T , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Fenotipo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Estudios RetrospectivosRESUMEN
OBJECTIVE: Longitudinal studies have indicated VCAM-1+ mesenchymal stem/stromal cells (MSCs) as promising resources in regenerative medicine, yet the abundance in gene expression is far from adequate in the advantaged and "discarded" hUC-MSCs. Thus, high-efficient preparation and systematic dissection of the signatures and biofunctions of the subpopulation is the prerequisite for large-scale clinical applications. MATERIALS AND METHODS: We primarily took advantage of a cytokine-based programming strategy for large-scale VCAM-1+ hUC-MSC generation (III-MSCs). Thereafter, we conducted multifaceted analyses including cytomorphology, immunophenotype, cell vitality, multilineage differentiation, whole-genome analysis, tube formation and Matrigel plug assay, lymphocyte activation and differentiation, and systemic transplantation for aplastic anaemia (AA) treatment. RESULTS: III-MSCs with high-proportioned VCAM-1 expression were obtained by combining IL-1ß, IL-4 with IFN-γ, which exhibited comparable immunophenotype with untreated hUC-MSCs (NT-MSCs) but revealed multidimensional superiorities both at the cellular and molecular levels. Simultaneously, systemic infusion of III-MSCs could significantly ameliorate clinicopathological features and finally help facilitate haematopoietic reconstruction and immunoregulation in AA mice. CONCLUSIONS: We have established a high-efficient procedure for large-scale generation of III-MSCs with preferable signatures and efficacy upon aplastic anaemia in mice. Our findings suggested that III-MSCs were advantageous sources with multifaceted characteristics for regenerative medicine.