RESUMEN
T-cell ALL (T-ALL) is an aggressive malignancy of T-cell progenitors. Although survival outcomes in T-ALL have greatly improved over the past 50 years, relapsed and refractory cases remain extremely challenging to treat and those who cannot tolerate intensive treatment continue to have poor outcomes. Furthermore, T-ALL has proven a more challenging immunotherapeutic target than B-ALL. In this review we explore our expanding knowledge of the basic biology of T-ALL and how this is paving the way for repurposing established treatments and the development of novel therapeutic approaches.
Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Antineoplásicos/administración & dosificación , Antineoplásicos Inmunológicos/uso terapéutico , Apoptosis/efectos de los fármacos , Arabinonucleósidos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Heterogeneidad Genética , Humanos , Inmunoterapia , Inmunoterapia Adoptiva , Inhibidores de las Cinasas Janus/uso terapéutico , Terapia Molecular Dirigida , Proteínas de Neoplasias/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptor Notch1/antagonistas & inhibidores , Receptores de Interleucina-7/antagonistas & inhibidores , Terapia Recuperativa/métodos , Transducción de Señal/efectos de los fármacos , Sulfonamidas/uso terapéutico , Terapias en Investigación/métodos , Terapias en Investigación/tendencias , Resultado del TratamientoRESUMEN
We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5+ cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5+ cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells.
RESUMEN
Following reduced intensity-conditioned allogeneic stem cell transplantation (RIC allo-SCT) for chronic lymphocytic leukaemia (CLL), there is an inverse relationship between relapse and extensive chronic graft-versus-host disease (GVHD). We evaluated outcomes in 50 consecutive patients with CLL using the approach of alemtuzumab-based RIC allo-SCT and pre-emptive donor lymphocyte infusions (DLI) for mixed chimerism or minimal residual disease (MRD), with the intention of reducing the risk of GVHD. Forty two patients had high-risk disease, including 30% with 17p deletion (17p-). Of patients who were not in complete remission (CR) entering transplant, 83% subsequently achieved MRD-negative CR. Both MRD detection and uncorrected mixed chimerism were associated with greater risks of treatment failure. Nine of sixteen patients receiving DLI for persistent or relapsed disease subsequently attained MRD-negative CR. With a median follow-up of 4.3 years, 4-year current progression-free survival was 65% and overall survival was 75% (60% and 61% in respectively, patients with 17p-). DLI was associated with a 29% cumulative incidence of severe GVHD and mortality of 6.4%. At last follow-up, 83% of patients in CR were off all immunosuppressive treatment. In conclusion, the directed delivery of allogeneic cellular therapy has the potential to induce durable remissions in high-risk CLL without incurring excessive GVHD.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Inmunoterapia Adoptiva , Leucemia Linfocítica Crónica de Células B/terapia , Adulto , Alemtuzumab , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos como Asunto/estadística & datos numéricos , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/epidemiología , Humanos , Inmunosupresores/uso terapéutico , Estimación de Kaplan-Meier , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/cirugía , Procedimientos de Reducción del Leucocitos , Transfusión de Linfocitos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto/estadística & datos numéricos , Neoplasia Residual , Pronóstico , Recurrencia , Estudios Retrospectivos , Medición de Riesgo , Terapia Recuperativa , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo , Resultado del TratamientoRESUMEN
B cell precursor acute lymphoblastic leukemia (BCP-ALL) is a malignant disorder of immature B lineage immune progenitors and is the commonest cancer in children. Despite treatment advances it remains a leading cause of death in childhood and response rates in adults remain poor. A preleukemic state predisposing children to BCP-ALL frequently arises in utero, with an incidence far higher than that of transformed leukemia, offering the potential for early intervention to prevent disease. Understanding the natural history of this disease requires an appreciation of how cell-extrinsic pressures, including microenvironment, immune surveillance and chemotherapy direct cell-intrinsic genetic and epigenetic evolution. In this review, we outline how microenvironmental factors interact with BCP-ALL at different stages of tumorigenesis and highlight emerging therapeutic avenues.
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Several studies have documented aberrant RNA editing patterns across multiple tumors across large patient cohorts from The Cancer Genome Atlas (TCGA). However, studies on understanding the role of RNA editing in acute myeloid leukemia (AML) have been limited to smaller sample sizes. Using high throughput transcriptomic data from the TCGA, we demonstrated higher levels of editing as a predictor of poor outcome within the AML patient samples. Moreover, differential editing patterns were observed across individual AML genotypes. We also could demonstrate a negative association between the degree of editing and mRNA abundance for some transcripts, identifying the potential regulatory potential of RNA-editing in altering gene expression in AML. Further edQTL analysis suggests potential cis-regulatory mechanisms in RNA editing variation. Our work suggests a functional and regulatory role of RNA editing in the pathogenesis of AML and we extended our analysis to gain insight into the factors influencing altered levels of editing.
RESUMEN
In vitro differentiation of human pluripotent stem cells (hPSCs) offers a genetically tractable system to examine the physiology and pathology of human tissue development and differentiation. We have used this approach to model the earliest stages of human B lineage development and characterize potential target cells for the in utero initiation of childhood B acute lymphoblastic leukemia. Herein, we detail critical aspects of the protocol including reagent validation, controls, and examples of surface markers used for analysis and cell sorting. For complete details on the use and execution of this protocol, please refer to Boiers et al. (2018).
Asunto(s)
Linfocitos B/citología , Técnicas de Cocultivo/métodos , Células Madre Pluripotentes/citología , Animales , Línea Celular , Separación Celular , Humanos , Leucemia Linfoide , RatonesRESUMEN
Loss-of-function mutations of EZH2, the enzymatic component of PRC2, have been associated with poor outcome and chemotherapy resistance in T-cell acute lymphoblastic leukemia (T-ALL). Using isogenic T-ALL cells, with and without CRISPR/Cas9-induced EZH2-inactivating mutations, we performed a cell-based synthetic lethal drug screen. EZH2-deficient cells exhibited increased sensitivity to structurally diverse inhibitors of CHK1, an interaction that could be validated genetically. Furthermore, small-molecule inhibition of CHK1 had efficacy in delaying tumor progression in isogenic EZH2-deficient, but not EZH2 wild-type, T-ALL cells in vivo, as well as in a primary cell model of PRC2-mutant ALL. Mechanistically, EZH2 deficiency resulted in a gene-expression signature of immature T-ALL cells, marked transcriptional upregulation of MYCN, increased replication stress, and enhanced dependency on CHK1 for cell survival. Finally, we demonstrate this phenotype is mediated through derepression of a distal PRC2-regulated MYCN enhancer. In conclusion, we highlight a novel and clinically exploitable pathway in high-risk EZH2-mutated T-ALL. SIGNIFICANCE: Loss-of-function mutations of PRC2 genes are associated with chemotherapy resistance in T-ALL, yet no specific therapy for this aggressive subtype is currently clinically available. Our work demonstrates that loss of EZH2 activity leads to MYCN-driven replication stress, resulting in increased sensitivity to CHK1 inhibition, a finding with immediate clinical relevance.This article is highlighted in the In This Issue feature, p. 890.
Asunto(s)
Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proliferación Celular , Humanos , Mutación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genéticaRESUMEN
Head injury is a common cause for hospital admission and additionally 250,000 UK inpatients fall during hospital admissions annually. Head injury most commonly occurs as a result of falls from standing height in older adults. Older adults are frequently frail and multi-morbid; many have indications for anticoagulation and antiplatelet agents. The haemorrhagic complications of head injury occur in up to 16% of anticoagulated patients sustaining a head injury. These patients suffer adverse outcomes from surgery as a result of medical complications. Although geriatric trauma models are evolving to meet the demand of an ageing trauma population, medical support to trauma services is commonly delivered by general physicians, many of whom lack experience and training in this field. Determining the role of surgery and interrupted anticoagulation requires careful personalised risk assessment. Appreciation of the opposing risks can be challenging; it requires an understanding of the evidence base in both surgery and medicine to rationalise decision making and inform communication. This article aims to provide an overview for the physician with clinical responsibility for patients who have sustained head injury.
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Traumatismos Craneocerebrales , Evaluación Geriátrica , Anciano , Anciano de 80 o más Años , Anciano Frágil , Fragilidad , Humanos , Rol del Médico , Guías de Práctica Clínica como AsuntoRESUMEN
ETV6-RUNX1 is associated with childhood acute B-lymphoblastic leukemia (cALL) functioning as a first-hit mutation that initiates a clinically silent pre-leukemia in utero. Because lineage commitment hierarchies differ between embryo and adult, and the impact of oncogenes is cell-context dependent, we hypothesized that the childhood affiliation of ETV6-RUNX1 cALL reflects its origins in a progenitor unique to embryonic life. We characterize the first emerging B cells in first-trimester human embryos, identifying a developmentally restricted CD19-IL-7R+ progenitor compartment, which transitions from a myeloid to lymphoid program during ontogeny. This developmental series is recapitulated in differentiating human pluripotent stem cells (hPSCs), thereby providing a model for the initiation of cALL. Genome-engineered hPSCs expressing ETV6-RUNX1 from the endogenous ETV6 locus show expansion of the CD19-IL-7R+ compartment, show a partial block in B lineage commitment, and produce proB cells with aberrant myeloid gene expression signatures and potential: features (collectively) consistent with a pre-leukemic state.
Asunto(s)
Linfocitos B/patología , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Desarrollo Embrionario , Regulación Leucémica de la Expresión Génica , Células Madre Pluripotentes Inducidas/patología , Células Mieloides/patología , Proteínas de Fusión Oncogénica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Enfermedad Aguda , Linfocitos B/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Femenino , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Modelos Biológicos , Células Mieloides/metabolismo , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Embarazo , Primer Trimestre del Embarazo , Receptores de Interleucina-7 , TranscriptomaRESUMEN
Accurate staging of classical Hodgkin lymphoma (CHL) directs treatment intensity. Functional imaging can detect marrow/bone involvement making the role of bone marrow biopsy (BMB) unclear. We assessed current UK practice in CHL staging by questionnaire and retrospectively analyzed patients staged at a single center with BMB and (18)F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). From 34 questionnaire responses 50% used FDG-PET/CT routinely. BMB was employed in 97% with advanced-stage and 30% of patients with limited-stage disease (70% of those not using routine FDG-PET/CT). Ten out of 50 patients were BM+, all of which were identified by FDG-PET/CT (PET+). Conventional BMB changed management in 2% of cases. There were no clinically significant FDG-PET/CT false positives. Conventional routine BMB staging in CHL is extremely insensitive. FDG-PET/CT can rule out marrow/bone involvement in CHL. In the FDG-PET/CT staging era BMB should be targeted to a minority of patients with FDG-PET/CT + bone/marrow uptake and only when management would be altered by the result.