RESUMEN
Acute leukemia is a group of aggressive hematological malignancies, with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) being the most common types. The biology of acute leukemia involves complex genetic and epigenetic alterations that lead to uncontrolled cell proliferation and resistance to apoptosis. Mitochondrial dysfunction is a feature of acute leukemia that results in altered energy production, unregulated cell death pathways, and increased cancer cell survival. Apoptosis, particularly via the mitochondrial pathway, is crucial for cellular homeostasis and cancer prevention. In acute leukemia, disruption of apoptosis is pivotal in disease development and progression, with elevated levels of anti-apoptotic proteins conferring a survival advantage to leukemia cells and promoting resistance to conventional therapies. Targeting mitochondrial apoptosis using BH3 mimetics and anti-apoptotic protein inhibitors is a viable therapeutic strategy. Alterations in the mitochondrial membrane potential, metabolism, and dynamics also contribute to the pathogenesis of acute leukemia. Continued research is vital for developing novel therapies and enhancing survival outcomes in patients with acute leukemia while minimizing the long-term adverse effects of treatment. In this narrative review, we provide a birds-eye view of the available scientific literature on the importance of mitochondria in acute leukemia, and discuss the role of BH3 mimetics in targeting the mitochondrial internal apoptotic machinery.
Asunto(s)
Apoptosis , Leucemia Mieloide Aguda , Mitocondrias , Humanos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Animales , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Potencial de la Membrana Mitocondrial/efectos de los fármacosRESUMEN
Acute lymphoblastic leukemia (ALL) is the most common type of malignancy in children. ALL prognosis after initial diagnosis is generally good; however, patients suffering from relapse have a poor outcome. The tumor microenvironment is recognized as an important contributor to relapse, yet the cell-cell interactions involved are complex and difficult to study in traditional experimental models. In the present study, we established an innovative larval zebrafish xenotransplantation model, that allows the analysis of leukemic cells (LCs) within an orthotopic niche using time-lapse microscopic and flow cytometric approaches. LCs homed, engrafted and proliferated within the hematopoietic niche at the time of transplant, the caudal hematopoietic tissue (CHT). A specific dissemination pattern of LCs within the CHT was recorded, as they extravasated over time and formed clusters close to the dorsal aorta. Interactions of LCs with macrophages and endothelial cells could be quantitatively characterized. This zebrafish model will allow the quantitative analysis of LCs in a functional and complex microenvironment, to study mechanisms of niche mediated leukemogenesis, leukemia maintenance and relapse development.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Microambiente Tumoral , Pez Cebra , Animales , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Humanos , Modelos Animales de Enfermedad , Comunicación Celular , Xenoinjertos , Nicho de Células Madre , Línea Celular Tumoral , Células Endoteliales/patología , Macrófagos/patología , Macrófagos/metabolismo , Trasplante HeterólogoRESUMEN
Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is characterized by reciprocal chromosomal translocation between chromosome 9 and 22, leading to the expression of constitutively active oncogenic BCR-ABL1 fusion protein. CXC chemokine receptor 4 (CXCR4) is essential for the survival of BCR-ABL1-transformed mouse pre-B cells, as the deletion of CXCR4 induces death in these cells. To investigate whether CXCR4 inhibition also effectively blocks BCR-ABL1-transformed cell growth in vitro, in this study, we explored an array of peptide-based inhibitors of CXCR4. The inhibitors were optimized derivatives of EPI-X4, an endogenous peptide antagonist of CXCR4. We observed that among all the candidates, EPI-X4 JM#170 (referred to as JM#170) effectively induced cell death in BCR-ABL1-transformed mouse B cells but had little effect on untransformed wild-type B cells. Importantly, AMD3100, a small molecule inhibitor of CXCR4, did not show this effect. Treatment with JM#170 induced transient JNK phosphorylation in BCR-ABL1-transformed cells, which in turn activated the intrinsic apoptotic pathway by inducing cJun, Bim, and Bax gene expressions. Combinatorial treatment of JM#170 with ABL1 kinase inhibitor Imatinib exerted a stronger killing effect on BCR-ABL1-transformed cells even at a lower dose of Imatinib. Surprisingly, JM#170 actively killed Sup-B15 cells, a BCR-ABL1+ human ALL cell line, but had no effect on the BCR-ABL1- 697 cell line. This suggests that the inhibitory effect of JM#170 is specific for BCR-ABL1+ ALL. Taken together, JM#170 emerges as a potent novel drug against Ph+ ALL.
Asunto(s)
Proteínas de Fusión bcr-abl , Receptores CXCR4 , Receptores CXCR4/metabolismo , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/genética , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/metabolismo , Animales , Ratones , Humanos , Péptidos/farmacología , Supervivencia Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Línea Celular Tumoral , Cromosoma Filadelfia/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologíaRESUMEN
microRNAs (miRNAs), tiny, non-coding RNA molecules, fine-tune the expression of target genes through interacting with mRNAs. These miRNAs are involved in a wide range of biological processes, encompassing cell division, death, blood cell production, and tumor development. When these miRNAs become dysfunctional, they can promote the invasion and spread of cancer cells in various human malignancies, including leukemia. Acute lymphoblastic leukemia (ALL), the preeminent malignancy affecting children, is a blood cancer marked by the uncontrollable growth of immature lymphoid cells that displace healthy blood precursors in the bone marrow. Despite a decline in ALL mortality rates over the past two decades, a significant proportion of deaths still results from a lack of effective diagnostic and prognostic markers that can guide treatment decisions and overcome drug resistance. The analysis of miRNA expression patterns in ALL could lead to more precise disease classification, earlier diagnosis, and better prognostic outcomes in the near future. The connection between miRNA dysfunction and the biology of ALL suggests that these molecules could represent promising therapeutic targets. Therefore, this review delves into the regulatory mechanisms of miRNAs in pediatric ALL, exploring how miRNA-based diagnostic, prognostic, and therapeutic strategies offer unique advantages and hold promise for clinical applications.
Asunto(s)
Biomarcadores de Tumor , MicroARNs , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , MicroARNs/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pronóstico , Biomarcadores de Tumor/genética , Niño , Regulación Leucémica de la Expresión Génica , Regulación Neoplásica de la Expresión GénicaRESUMEN
USP7 is an attractive therapeutic target for cancers, especially for acute lymphoblastic leukemia (ALL) with wild-type p53. Herein, we report the discovery of XM-U-14 as a highly potent, selective and efficacious USP7 proteolysis-targeting chimera degrader. XM-U-14 achieves DC50 values of 0.74 nM and Dmax of 93% in inducing USP7 degradation in RS4;11 cell lines, and also significantly inhibits ALL cell growth. XM-U-14 even at 5 mg/kg dosed daily effectively inhibits RS4;11 tumor growth with 64.7% tumor regressions and causes no signs of toxicity in mice. XM-U-14 is a promising USP7 degrader for further optimization for ALL treatment.
Asunto(s)
Antineoplásicos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Peptidasa Específica de Ubiquitina 7 , Peptidasa Específica de Ubiquitina 7/metabolismo , Peptidasa Específica de Ubiquitina 7/antagonistas & inhibidores , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Animales , Ratones , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Relación Estructura-Actividad , Proteolisis/efectos de los fármacosRESUMEN
PURPOSE: BCR::ABL1 quantification is widely regarded as the standard for monitoring measurable residual disease (MRD) in Philadelphia chromosome-positive (Ph+) ALL. However, recent evidence of BCR::ABL1 multilineage involvement questions the significance of BCR::ABL1 MRD. We aimed to define the prognostic role of MRD as assessed by BCR::ABL1 or lymphoid-specific immunoglobulin/T-cell receptor (IG/TR) gene markers. PATIENTS AND METHODS: We conducted BCR::ABL1 and IG/TR quantification after each treatment cycle in 264 patients treated in the GRAAPH-2014 trial, which used four cycles of reduced-intensity chemotherapy with nilotinib, followed by hematopoietic stem-cell transplantation (HSCT). RESULTS: Comparing BCR::ABL1 and IG/TR MRD revealed residual BCR::ABL1-positive non-ALL cells in 98 (43%) of 228 patients, defining multilineage Ph+ ALL. Despite poorer BCR::ABL1 responses, patients with multilineage Ph+ ALL had similar disease-free survival (DFS; hazard ratio [HR], 0.83 [95% CI, 0.49 to 1.41]; P = .50). Although BCR::ABL1 response failed to predict outcomes, IG/TR positivity (≥0.01%) was strongly associated with lower DFS (after cycle 2, HR, 2.49 [95% CI, 1.40 to 4.40]; P = .002; after cycle 4, HR, 4.13 [95% CI, 1.82 to 9.38]; P = .001). In multivariable analysis, both IG/TR positivity after cycle 2 and initial WBC count ≥30 × 109/L predicted poorer DFS, enabling to define a high-risk group having a 4-year DFS of 56.5% compared with 87.6% (HR, 3.72 [95% CI, 1.93 to 7.15]; P < .001). Moreover, allogeneic HSCT significantly improved DFS in the high-risk group (HR, 0.33 [95% CI, 0.18 to 0.60]; P < .001), whereas the standard-risk group had favorable outcomes regardless of allogeneic HSCT. CONCLUSION: Our findings challenge the significance of BCR::ABL1 monitoring in adult Ph+ ALL and demonstrate the prognostic role of IG/TR MRD. This study provides a framework for using MRD to guide treatment strategies in adults with Ph+ ALL.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Neoplasia Residual , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Adulto , Masculino , Femenino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pirimidinas/uso terapéutico , Adulto Joven , Proteínas de Fusión bcr-abl/genética , Anciano , Pronóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adolescente , Proteínas Proto-Oncogénicas c-abl/genéticaRESUMEN
The MDM2 oncogene is amplified and/or overexpressed in various human cancers and elevated expression of MDM2 protein acts as a survival factor promoting cancer progression through both p53-dependent and -independent pathways. Here, we report a novel small-molecule chemical compound (MX69-102) that we identified to induce MDM2 protein degradation, resulting in reactivation of p53, inhibition of XIAP, and potent cell growth inhibition and apoptosis in MDM2-overexpressing acute lymphoblastic leukemia (ALL) in vitro and in vivo. We have previously identified a compound (MX69) that binds to the MDM2 C-terminal RING domain and induces MDM2 protein degradation. In the present study, we performed structural modifications of MX69 and selected analog MX69-102, showing increased MDM2-targeting activity. MX69-102 exhibited significantly enhanced inhibitory and apoptotic effects on a group of MDM2-overexpressing ALL cell lines in vitro with IC50 values of about 0.2 µM, representing an approximately 38-fold increase in activity compared to MX69. MX69-102 also showed effective inhibition on xenografted human MDM2-overexpressing ALL in SCID mice. Importantly, MX69-102 had minimal or no inhibitory effect on normal human hematopoiesis in vitro and was very well tolerated in vivo in animal models. Based on the strong inhibitory and apoptotic activity against MDM2-overexpressing ALL, along with minimal or no toxicity to normal cells/tissues, MX69-102 is a candidate for further development as a novel MDM2-targeted therapeutic drug for refractory/MDM2-overexpressing ALL.
Asunto(s)
Apoptosis , Ratones SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras , Proteínas Proto-Oncogénicas c-mdm2 , Proteína p53 Supresora de Tumor , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/genética , Humanos , Animales , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Apoptosis/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Línea Celular Tumoral , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Proteolisis/efectos de los fármacos , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Relación Dosis-Respuesta a Droga , Ratones , Femenino , Relación Estructura-ActividadRESUMEN
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Current chemotherapy treatment regimens have improved survival rates to approximately 80%; however, resistance development remains the primary cause of treatment failure, affecting around 20% of cases. Some studies indicate that loss of the phosphatase and tensin homolog (PTEN) leads to deregulation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, increasing the expression of proteins involved in chemoresistance. PTEN loss results in deregulation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and induces hypoxia-inducible factor 1-alpha (HIF-1α) expression in various cancers. Additionally, it triggers upregulation of the Yin Yang 1 (YY1) transcription factor, leading to chemoresistance mediated by glycoprotein p-170 (Gp-170). The aim of this study was to investigate the role of the PTEN/NF-κB axis in YY1 regulation via HIF-1α and its involvement in ALL. A PTEN inhibitor was administered in RS4;11 cells, followed by the evaluation of PTEN, NF-κB, HIF-1α, YY1, and Gp-170 expression, along with chemoresistance assessment. PTEN, HIF-1α, and YY1 expression levels were assessed in the peripheral blood mononuclear cells (PBMC) from pediatric ALL patients. The results reveal that the inhibition of PTEN activity significantly increases the expression of pAkt and NF-κB, which is consistent with the increase in the expression of HIF-1α and YY1 in RS4;11 cells. In turn, this inhibition increases the expression of the glycoprotein Gp-170, affecting doxorubicin accumulation in the cells treated with the inhibitor. Samples from pediatric ALL patients exhibit PTEN expression and higher HIF-1α and YY1 expression compared to controls. PTEN/Akt/NF-κB axis plays a critical role in the regulation of YY1 through HIF-1α, and this mechanism contributes to Gp-170-mediated chemoresistance in pediatric ALL.
Asunto(s)
Resistencia a Antineoplásicos , Subunidad alfa del Factor 1 Inducible por Hipoxia , Fosfohidrolasa PTEN , Leucemia-Linfoma Linfoblástico de Células Precursoras , Factor de Transcripción YY1 , Humanos , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Factor de Transcripción YY1/metabolismo , Factor de Transcripción YY1/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Resistencia a Antineoplásicos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Niño , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , FN-kappa B/metabolismo , Masculino , FemeninoRESUMEN
Children with acute lymphocytic leukemia rarely develop secondary hematological neoplasms. A 5-year-old boy was diagnosed with standard-risk precursor B-cell acute lymphocytic leukemia. The patient exhibited aberrant chromosomal changes in the bone marrow at 6 months postchemotherapy: 46,XY,der(6) t(1;6)(q12;p22) dup(6)(p22p12)[15]. Clinically, the patient has sustained complete remission and has not developed myeloid malignancy over the subsequent period (27 mo). The cytogenetic aberration was observed in 11% of CD34+ cells isolated from the bone marrow. We infer that the abnormal clone acquires self-renewal potency, differentiation, and growth advantage. Further long-term observation is needed to determine the nature of this cytogenetic aberration.
Asunto(s)
Hematopoyesis Clonal , Humanos , Masculino , Niño , Preescolar , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Aberraciones Cromosómicas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/tratamiento farmacológicoRESUMEN
BACKGROUND: The objective of this study is to assess the concordance and added value of combined comparative genomic hybridization plus single-nucleotide polymorphism microarray (CGH/SNP) analyses in pediatric acute lymphoblastic leukemia (ALL) risk stratification compared to conventional cytogenetic methods. PROCEDURE: This is a retrospective study that included patients aged 1-18 years diagnosed with de novo ALL at Sainte-Justine Hospital between 2016 and 2021. Results from conventional cytogenetic and molecular analyses were collected and compared to those of CGH/SNP. RESULTS: A total of 135 ALL patients were included. Sample failures or non-diagnostic analyses occurred in 17.8% cases with G-banding karyotypes versus 1.5% cases with CGH/SNP. The mean turnaround time for results was significantly faster for CGH/SNP than karyotype with 5.8 versus 10.7 days, respectively. The comparison of ploidy assessment by CGH/SNP and G-banding karyotype showed strong concordance (r = .82, p < .001, r2 = .68). Furthermore, G-banding karyotype did not detect additional clinically relevant aberrations that were missed by the combined analysis of CGH/SNP and fluorescence in situ hybridization. The most common gene alterations detected by CGH/SNP were deletions involving CDKN2A (35.8%), ETV6 (31.3%), CDKN2B (28.4%), PAX5 (20.1%), IKZF1 (12.7%), and copy-neutral loss of heterozygosity (CN-LOH) of 9p (9.0%). Among these, only ETV6 deletion was found to have a significant prognostic impact with superior event-free survival in both univariate and multivariate analyses (adjusted hazard ratio 0.08, 95% confidence interval: 0.01-0.50, p = .02). CONCLUSION: CGH/SNP provided faster, reliable, and highly concordant results than those obtained by conventional cytogenetics. CGH/SNP identified recurrent gene deletions in pediatric ALL, of which ETV6 deletion conferred a favorable prognosis.
Asunto(s)
Hibridación Genómica Comparativa , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Niño , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Femenino , Preescolar , Masculino , Adolescente , Lactante , Estudios Retrospectivos , Hibridación Genómica Comparativa/métodos , Pronóstico , Medición de Riesgo/métodos , Estudios de Seguimiento , Tasa de SupervivenciaRESUMEN
BACKGROUND: Accurate estimation of body composition, particularly, Body Cell Mass (BCM), which is independent of hydration status is important in children with cancer. This study aimed to accurately measure the anthropometry and body composition of children with Acute Lymphoblastic Leukaemia (ALL) at diagnosis and compare them with healthy children from South India. METHODS: This was a cross-sectional study in children aged 2 to 8 y with ALL from St. John's Medical College Hospital, Bengaluru, and age and sex-matched, normal-weight children recruited as controls from communities. Anthropometry (weight, height, circumferences), skinfolds and body composition measurements using a whole-body potassium counter were performed. Body mass index-for-age, weight and height for age z-scores were calculated using WHO child growth standards. Biochemical markers, dietary intake and physical activity details were recorded. Categorical and continuous variables were analyzed by chi-square and independent t-tests respectively. Results: The mean age of the children with ALL (n = 39) was 4.6±1.9 y and control group (n=39) was 4.7±1.9 y; 61.5% were boys. The prevalence of underweight, overweight/obesity and stunting were 17.9%, 7.7%, and 10.3% respectively. The mean weight and height, of children with ALL and children in the control group were 16.8±6.2 kg and 16.4±4.1 kg, 104.3±14.9 cm and 105.1±12.2 cm, respectively with no statistical difference. Children with ALL showed lower body cell mass index kg/m2 (4.6± 0.8), compared to children in the control group (4.7±0.9) p=0.527, but higher fat mass index kg/m2 (3.6±1.1 vs. 3.4±0.8) p=0.276. CONCLUSION: At diagnosis, anthropometric and body composition measurements were similar between children with ALL and children in the control group. The BCM showed a non-significant trend of being lower in children with ALL, which requires close monitoring during treatment. Evaluating early-stage nutritional status and body composition can help in planning appropriate interventions during treatment to prevent long term non-communicable diseases.
Asunto(s)
Composición Corporal , Índice de Masa Corporal , Estado Nutricional , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Masculino , Estudios Transversales , Femenino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Niño , Preescolar , India/epidemiología , Estudios de Casos y Controles , Pronóstico , Estudios de Seguimiento , Delgadez/epidemiología , Delgadez/diagnóstico , Peso Corporal , Sobrepeso/epidemiologíaRESUMEN
Natural killer (NK) cells play a crucial role in innate immunity, particularly in combating infections and tumors. However, in hematological cancers, NK cells often exhibit impaired functions. Therefore, it is very important to activate its endosomal Toll-like receptors (TLRs) as a potential strategy to restore its antitumor activity. We stimulated NK cells from the peripheral blood mononuclear cells from children with acute lymphoblastic leukemia and NK cells isolated, and the NK cells were stimulated with specific TLR ligands (Poly I:C, Imiquimod, R848, and ODN2006) and we evaluated changes in IFN-γ, CD107a, NKG2D, NKp44 expression, Granzyme B secretion, cytokine/chemokine release, and cytotoxic activity. Results revealed that Poly I:C and Imiquimod enhanced the activation of both immunoregulatory and cytotoxic NK cells, increasing IFN-γ, CD107a, NKG2D, and NKp44 expression. R848 activated immunoregulatory NK cells, while ODN2006 boosted CD107a, NKp44, NKG2D, and IFN-γ secretion in cytotoxic NK cells. R848 also increased the secretion of seven cytokines/chemokines. Importantly, R848 and ODN 2006 significantly improved cytotoxicity against leukemic cells. Overall, TLR stimulation enhances NK cell activation, suggesting TLR8 (R848) and TLR9 (ODN 2006) ligands as promising candidates for antitumor immunotherapy.
Asunto(s)
Imiquimod , Células Asesinas Naturales , Activación de Linfocitos , Poli I-C , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores Toll-Like , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Poli I-C/farmacología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Imiquimod/farmacología , Receptores Toll-Like/metabolismo , Receptores Toll-Like/agonistas , Niño , Oligodesoxirribonucleótidos/farmacología , Citocinas/metabolismo , Femenino , Interferón gamma/metabolismo , Masculino , Imidazoles/farmacología , Citotoxicidad Inmunológica/efectos de los fármacos , Preescolar , Agonistas de los Receptores Toll-LikeRESUMEN
BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common type of blood cancer in children. Aberrant expression of long noncoding RNAs (lncRNAs) may set stages for ALL development. LncRNAs are emerging as a novel diagnostic and prognostic biomarker for ALL. Herein, we aimed to evaluate the expression of lncRNA GJA9-MYCBP and PVT1 in blood samples of ALL and healthy individuals. METHODS: As a case-control study, 40 pairs of ALL and healthy individual samples were used. The expression of MYC and each candidate lncRNA was measured using quantitative real-time PCR. Any possible association between the expression of putative noncoding RNAs and clinicopathological characteristics was also evaluated. RESULTS: LncRNA GJA9-MYCBP and PVT1 were significantly upregulated in ALL samples compared with healthy ones. Similarly, mRNA levels of MYC were increased in ALL samples than control ones. Receiver operating characteristic curve analysis indicated a satisfactory diagnostic efficacy (p-value <.0001), suggesting that lncRNA GJA9-MYCBP and PVT1 may serve as a diagnostic biomarker for ALL. Linear regression analysis unveiled positive correlations between the expression level of MYC and lncRNA GJA9-MYCBP and PVT1 in ALL patients (p-values <.01). CONCLUSIONS: In this study, we provided approval for the clinical diagnostic significance of lncRNA GJA9-MYCBP and PVT1that their upregulations may be a diagnostic biomarker for ALL.
Asunto(s)
Biomarcadores de Tumor , Leucemia-Linfoma Linfoblástico de Células Precursoras , ARN Largo no Codificante , Regulación hacia Arriba , Humanos , ARN Largo no Codificante/genética , Biomarcadores de Tumor/genética , Masculino , Femenino , Estudios de Casos y Controles , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Niño , Pronóstico , Preescolar , Adolescente , Curva ROC , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismoRESUMEN
BACKGROUND: Acute lymphoblastic leukemia (ALL) is one of the most common malignancies among children. Despite success in frontline treatment, 20% of children will relapse or show resistance to treatment. AIM: The aim of this study is to evaluate the clinical characteristics of children diagnosed and treated for refractory or relapsed ALL and determine 3-year overall survival (OS) outcomes. METHOD: This study involved a retrospective chart review of patients aged 1-14 years diagnosed with ALL during January 2002 to December 2018. Data were extracted for baseline characteristics at diagnosis and at relapse. RESULTS: A total of 347 newly diagnosed children with ALL were identified, among whom there were three induction failures (IF) and 28 relapses, resulting in a cohort of 31 patients with a relapse rate of 9%. The male-to-female ratio was 4.16:1, and the mean duration of first complete remission (CR1) was 26 months. Fifteen (48%) patients relapsed ≤18 months, 7 (23%) during 18-36 months, and 9 (29%) relapsed >36 months of IF or CR1. Nineteen patients (61%) had isolated bone marrow (BM) relapse, 7 (23%) patients experienced isolated extramedullary relapse (5 isolated CNS relapse and 2 isolated testicular relapse), and 5 (16%) patients experienced BM involvement with other sites (4 BM + CNS and 1 BM + testis). The 3-year OS of the cohort was 62.3%, while in patients with CR post first-salvage therapy, a 3-year OS of 79.5% was observed (p value <.05 compared with patients who did not achieve remission post first-salvage therapy, 3-year OS: 46.4%). The same statistical difference was observed in 3-year OS when comparing the duration of remission of CR prior to relapse: ≤18 months, 33.2%; 18-36 months, 66.7%; and >36 months, 87.5%. The same trend continued when comparing 3-year OS based on risk stratification at relapse: low risk (LR), 83.3%; intermediate risk (IR), 80%; and high risk (HR), 44.8%. CONCLUSION: The incidence and outcomes reported are comparable to internationally reported data regarding the duration of CR1. Risk stratification at relapse and remission status post-salvage therapy were identified as significant prognostic factors for survival. No survival difference was observed among patients who received hematopoietic stem cell transplantation after induction compared with those who received chemotherapy, which could be attributed to the smaller sample size, warranting a multi-institutional observational study. These findings corroborate the need for novel therapies and treatment approaches.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Centros de Atención Terciaria , Humanos , Masculino , Femenino , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Niño , Estudios Retrospectivos , Preescolar , Adolescente , Lactante , Centros de Atención Terciaria/estadística & datos numéricos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/epidemiología , Inducción de Remisión , Tasa de Supervivencia , Resultado del Tratamiento , Pronóstico , Terapia Recuperativa , Resistencia a AntineoplásicosRESUMEN
The bone marrow overproduces immature cells in the malignancy known as Acute Lymphoblastic Leukemia (ALL). In the United States, about 6500 occurrences of ALL are diagnosed each year in both children and adults, comprising nearly 25% of pediatric cancer cases. Recently, many computer-assisted diagnosis (CAD) systems have been proposed to aid hematologists in reducing workload, providing correct results, and managing enormous volumes of data. Traditional CAD systems rely on hematologists' expertise, specialized features, and subject knowledge. Utilizing early detection of ALL can aid radiologists and doctors in making medical decisions. In this study, Deep Dilated Residual Convolutional Neural Network (DDRNet) is presented for the classification of blood cell images, focusing on eosinophils, lymphocytes, monocytes, and neutrophils. To tackle challenges like vanishing gradients and enhance feature extraction, the model incorporates Deep Residual Dilated Blocks (DRDB) for faster convergence. Conventional residual blocks are strategically placed between layers to preserve original information and extract general feature maps. Global and Local Feature Enhancement Blocks (GLFEB) balance weak contributions from shallow layers for improved feature normalization. The global feature from the initial convolution layer, when combined with GLFEB-processed features, reinforces classification representations. The Tanh function introduces non-linearity. A Channel and Spatial Attention Block (CSAB) is integrated into the neural network to emphasize or minimize specific feature channels, while fully connected layers transform the data. The use of a sigmoid activation function concentrates on relevant features for multiclass lymphoblastic leukemia classification The model was analyzed with Kaggle dataset (16,249 images) categorized into four classes, with a training and testing ratio of 80:20. Experimental results showed that DRDB, GLFEB and CSAB blocks' feature discrimination ability boosted the DDRNet model F1 score to 0.96 with minimal computational complexity and optimum classification accuracy of 99.86% and 91.98% for training and testing data. The DDRNet model stands out from existing methods due to its high testing accuracy of 91.98%, F1 score of 0.96, minimal computational complexity, and enhanced feature discrimination ability. The strategic combination of these blocks (DRDB, GLFEB, and CSAB) are designed to address specific challenges in the classification process, leading to improved discrimination of features crucial for accurate multi-class blood cell image identification. Their effective integration within the model contributes to the superior performance of DDRNet.
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Aprendizaje Profundo , Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/clasificación , Humanos , Redes Neurales de la Computación , Diagnóstico por Computador/métodos , NiñoRESUMEN
Deregulated apoptosis signaling is characteristic for many cancers and contributes to leukemogenesis and treatment failure in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Apoptosis is controlled by different pro- and anti-apoptotic molecules. Inhibition of anti-apoptotic molecules like B-cell lymphoma 2 (BCL-2) has been developed as therapeutic strategy. Venetoclax (VEN), a selective BCL-2 inhibitor has shown clinical activity in different lymphoid malignancies and is currently evaluated in first clinical trials in BCP-ALL. However, insensitivity to VEN has been described constituting a major clinical concern. Here, we addressed and modeled VEN-resistance in BCP-ALL, investigated the underlying mechanisms in cell lines and patient-derived xenograft (PDX) samples and identified potential strategies to overcome VEN-insensitivity. Leukemia lines with VEN-specific resistance were generated in vitro and further characterized using RNA-seq analysis. Interestingly, gene sets annotated to the citric/tricarboxylic acid cycle and the respiratory electron transport chain were significantly enriched and upregulated, indicating increased mitochondrial metabolism in VEN-resistant ALL. Metabolic profiling showed sustained high mitochondrial metabolism in VEN-resistant lines as compared to control lines. Accordingly, primary PDX-ALL samples with intrinsic VEN-insensitivity showed higher oxygen consumption and ATP production rates, further highlighting that increased mitochondrial activity is a characteristic feature of VEN-resistant ALL. VEN-resistant PDX-ALL showed significant higher mitochondrial DNA content and differed in mitochondria morphology with significantly larger and elongated structures, further corroborating our finding of augmented mitochondrial metabolism upon VEN-resistance. Using Oligomycin, an inhibitor of the complex V/ATPase subunit, we found synergistic activity and apoptosis induction in VEN-resistant BCP-ALL cell lines and PDX samples, demonstrating that acquired and intrinsic VEN-insensitivity can be overcome by co-targeting BCL-2 and the OxPhos pathway. These findings of reprogrammed, high mitochondrial metabolism in VEN-resistance and synergistic activity upon co-targeting BCL-2 and oxidative phosphorylation strongly suggest further preclinical and potential clinical evaluation in VEN-resistant BCP-ALL.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes , Resistencia a Antineoplásicos , Mitocondrias , Fosforilación Oxidativa , Leucemia-Linfoma Linfoblástico de Células Precursoras , Sulfonamidas , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Humanos , Fosforilación Oxidativa/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Sulfonamidas/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animales , Línea Celular Tumoral , Ratones , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genéticaRESUMEN
BACKGROUND: The BCR::ABL1 is a hallmark of chronic myeloid leukemia (CML) and is also found in acute lymphoblastic leukemia (ALL). Most genomic breaks on the BCR side occur in two regions - Major and minor - leading to p210 and p190 fusion proteins, respectively. METHODS: By multiplex long-distance PCR or next-generation sequencing technology we characterized the BCR::ABL1 genomic fusion in 971 patients (adults and children, with CML and ALL: pediatric ALL: n = 353; pediatric CML: n = 197; adult ALL: n = 166; adult CML: n = 255 patients) and designed "Break-App" web tool to allow visualization and various analyses of the breakpoints. Pearson's Chi-Squared test, Kolmogorov-Smirnov test and logistic regression were used for statistical analyses. RESULTS: Detailed analysis showed a non-random distribution of breaks in both BCR regions, whereas ABL1 breaks were distributed more evenly. However, we found a significant difference in the distribution of breaks between CML and ALL. We found no association of breakpoints with any type of interspersed repeats or DNA motifs. With a few exceptions, the primary structure of the fusions suggests non-homologous end joining being responsible for the BCR and ABL1 gene fusions. Analysis of reciprocal ABL1::BCR fusions in 453 patients showed mostly balanced translocations without major deletions or duplications. CONCLUSIONS: Taken together, our data suggest that physical colocalization and chromatin accessibility, which change with the developmental stage of the cell (hence the difference between ALL and CML), are more critical factors influencing breakpoint localization than presence of specific DNA motifs.
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Puntos de Rotura del Cromosoma , Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Proteínas de Fusión bcr-abl/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Adulto , Niño , Masculino , Femenino , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
BACKGROUND: Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) refers to ALL patients with t(9;22) cytogenetic abnormalities, accounting for about 25% of ALL. Lung adenocarcinoma (LUAD) is the most common pathological type of non-small-cell lung cancer, which has a frequency of approximately 45% cases with mutations in EGFR. Both Ph+ ALL and EGFR mutant LUAD are involved in the pathogenesis of the abnormal activation of the tyrosine kinase pathway. Although the second primary hematological malignancy after the treatment of solid tumors is common in clinics, the synchronous multiple primary malignant tumors of hematological malignancy overlap solid tumors are uncommon, even both tumors involved in the pathogenesis of the abnormal activation of the tyrosine kinase pathway are extremely rare. CASE PRESENTATION: An 84-year-old man with fatigue and dizziness was diagnosed with Ph+ ALL. Meanwhile, a chest CT indicated a space-occupying lesions, characterized by the presence of void, in the right lower lope with the enlargement of mediastinal lymph node and right pleural effusion. After a few weeks, the patient was diagnosed with LUAD with EGFR exon 19 mutation. Both tyrosine kinase inhibitors (TKI) (Flumatinib) and EGFR-TKI (Oxertinib) was used for the patients, and finally have controlled both diseases. CONCLUSION: As far as we know, we for the first time reported a case of Ph+ ALL and EGFR mutant LUAD synchronous overlap, of which pathogenesis is related to abnormal tyrosine kinase activation. This patient was successfully treated with two different TKIs without serious adverse events.
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Adenocarcinoma del Pulmón , Receptores ErbB , Neoplasias Pulmonares , Mutación , Leucemia-Linfoma Linfoblástico de Células Precursoras , Inhibidores de Proteínas Quinasas , Humanos , Masculino , Anciano de 80 o más Años , Receptores ErbB/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/complicaciones , Cromosoma FiladelfiaRESUMEN
PURPOSE OF REVIEW: Measurable residual disease (MRD) is integral in the management of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). This review discusses the current methods used to evaluate MRD as well as the interpretation, significance, and incorporation of MRD in current practice. RECENT FINDINGS: New molecular technologies have allowed the detection of MRD to levels as low as 10- 6. The most used techniques to evaluate MRD are multiparametric flow cytometry (MFC), quantitative reverse transcription polymerase chain reaction (RT-qPCR), and high-throughput next-generation sequencing (NGS). Each method varies in terms of advantages, disadvantages, and MRD sensitivity. MRD negativity after induction treatment and after allogeneic hematopoietic cell transplantation (HCT) is an important prognostic marker that has consistently been shown to be associated with improved outcomes. Blinatumomab, a new targeted therapy for Ph + ALL, demonstrates high efficacy in eradicating MRD and improving patient outcomes. In the relapsed/refractory setting, the use of inotuzumab ozogamicin and tisagenlecleucel has shown promise in eradicating MRD. The presence of MRD has become an important predictive measure in Ph + ALL. Current studies evaluate the use of MRD in treatment decisions, especially in expanding therapeutic options for Ph + ALL, including tyrosine kinase inhibitors, targeted antibody therapies, chimeric antigen receptor cell therapy, and HCT.