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1.
Nature ; 601(7891): 125-131, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34880496

RESUMEN

All cancers emerge after a period of clonal selection and subsequent clonal expansion. Although the evolutionary principles imparted by genetic intratumour heterogeneity are becoming increasingly clear1, little is known about the non-genetic mechanisms that contribute to intratumour heterogeneity and malignant clonal fitness2. Here, using single-cell profiling and lineage tracing (SPLINTR)-an expressed barcoding strategy-we trace isogenic clones in three clinically relevant mouse models of acute myeloid leukaemia. We find that malignant clonal dominance is a cell-intrinsic and heritable property that is facilitated by the repression of antigen presentation and increased expression of the secretory leukocyte peptidase inhibitor gene (Slpi), which we genetically validate as a regulator of acute myeloid leukaemia. Increased transcriptional heterogeneity is a feature that enables clonal fitness in diverse tissues and immune microenvironments and in the context of clonal competition between genetically distinct clones. Similar to haematopoietic stem cells3, leukaemia stem cells (LSCs) display heritable clone-intrinsic properties of high, and low clonal output that contribute to the overall tumour mass. We demonstrate that LSC clonal output dictates sensitivity to chemotherapy and, although high- and low-output clones adapt differently to therapeutic pressure, they coordinately emerge from minimal residual disease with increased expression of the LSC program. Together, these data provide fundamental insights into the non-genetic transcriptional processes that underpin malignant clonal fitness and may inform future therapeutic strategies.


Asunto(s)
Competencia Celular , Células Clonales/patología , Leucemia Mieloide Aguda/patología , Análisis de la Célula Individual , Animales , Competencia Celular/efectos de los fármacos , Línea Celular , Linaje de la Célula/efectos de los fármacos , Células Clonales/efectos de los fármacos , Células Clonales/metabolismo , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Ratones , Ratones Endogámicos C57BL , Inhibidor Secretorio de Peptidasas Leucocitarias/metabolismo
2.
Blood ; 134(22): 1891-1901, 2019 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-31697822

RESUMEN

A hallmark of acute myeloid leukemia (AML) is epigenetic dysregulation, which is initiated by recurrent translocations and/or mutations in transcription factors and chromatin regulators. This manifests as a block in myeloid differentiation and an increase in malignant self-renewal. These common features of AML have led to widespread optimism that epigenetic therapies would dramatically change the natural history of this disease. Although preclinical studies with these drugs fueled this optimism, results from early clinical trials have offered a more sobering message. Here, we provide an overview of epigenetic therapies that are currently approved by therapeutic regulatory authorities across the world and those undergoing early-phase clinical trials. We also discuss the conceptual and molecular factors that may explain some of the disparity between the bench and bedside, as well as emerging avenues for combining the current generation of epigenetic therapies with other classes of agents and the development of novel epigenetic therapies. With further research and development of this exciting class of drugs, we may finally be able to dramatically improve outcomes for patients afflicted with this aggressive and often incurable malignancy.


Asunto(s)
Antineoplásicos/uso terapéutico , Epigénesis Genética/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Ensayos Clínicos como Asunto , Humanos
3.
Cell Rep Methods ; 4(5): 100763, 2024 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-38670101

RESUMEN

Cellular barcoding is a lineage-tracing methodology that couples heritable synthetic barcodes to high-throughput sequencing, enabling the accurate tracing of cell lineages across a range of biological contexts. Recent studies have extended these methods by incorporating lineage information into single-cell or spatial transcriptomics readouts. Leveraging the rich biological information within these datasets requires dedicated computational tools for dataset pre-processing and analysis. Here, we present BARtab, a portable and scalable Nextflow pipeline, and bartools, an open-source R package, designed to provide an integrated end-to-end cellular barcoding analysis toolkit. BARtab and bartools contain methods to simplify the extraction, quality control, analysis, and visualization of lineage barcodes from population-level, single-cell, and spatial transcriptomics experiments. We showcase the utility of our integrated BARtab and bartools workflow via the analysis of exemplar bulk, single-cell, and spatial transcriptomics experiments containing cellular barcoding information.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Análisis de la Célula Individual , Transcriptoma , Análisis de la Célula Individual/métodos , Humanos , Programas Informáticos , Código de Barras del ADN Taxonómico/métodos , Genoma/genética , Linaje de la Célula/genética , Perfilación de la Expresión Génica/métodos , Biología Computacional/métodos , Animales
4.
Stem Cell Reports ; 19(8): 1189-1204, 2024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-39094562

RESUMEN

It has been proposed that adult hematopoiesis is sustained by multipotent progenitors (MPPs) specified during embryogenesis. Adult-like hematopoietic stem cell (HSC) and MPP immunophenotypes are present in the fetus, but knowledge of their functional capacity is incomplete. We found that fetal MPP populations were functionally similar to adult cells, albeit with some differences in lymphoid output. Clonal assessment revealed that lineage biases arose from differences in patterns of single-/bi-lineage differentiation. Long-term (LT)- and short-term (ST)-HSC populations were distinguished from MPPs according to capacity for clonal multilineage differentiation. We discovered that a large cohort of long-term repopulating units (LT-RUs) resides within the ST-HSC population; a significant portion of these were labeled using Flt3-cre. This finding has two implications: (1) use of the CD150+ LT-HSC immunophenotype alone will significantly underestimate the size and diversity of the LT-RU pool and (2) LT-RUs in the ST-HSC population have the attributes required to persist into adulthood.


Asunto(s)
Linaje de la Célula , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas , Animales , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Ratones , Diferenciación Celular , Feto/citología , Inmunofenotipificación , Hematopoyesis , Células Clonales/citología
5.
Cancer Cell ; 40(10): 1190-1206.e9, 2022 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-36179686

RESUMEN

There is increasing recognition of the prognostic significance of tumor cell major histocompatibility complex (MHC) class II expression in anti-cancer immunity. Relapse of acute myeloid leukemia (AML) following allogeneic stem cell transplantation (alloSCT) has recently been linked to MHC class II silencing in leukemic blasts; however, the regulation of MHC class II expression remains incompletely understood. Utilizing unbiased CRISPR-Cas9 screens, we identify that the C-terminal binding protein (CtBP) complex transcriptionally represses MHC class II pathway genes, while the E3 ubiquitin ligase complex component FBXO11 mediates degradation of CIITA, the principal transcription factor regulating MHC class II expression. Targeting these repressive mechanisms selectively induces MHC class II upregulation across a range of AML cell lines. Functionally, MHC class II+ leukemic blasts stimulate antigen-dependent CD4+ T cell activation and potent anti-tumor immune responses, providing fundamental insights into the graft-versus-leukemia effect. These findings establish the rationale for therapeutic strategies aimed at restoring tumor-specific MHC class II expression to salvage AML relapse post-alloSCT and also potentially to enhance immunotherapy outcomes in non-myeloid malignancies.


Asunto(s)
Proteínas F-Box , Leucemia Mieloide Aguda , Oxidorreductasas de Alcohol , Proteínas de Unión al ADN , Proteínas F-Box/genética , Antígenos HLA/genética , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Activación de Linfocitos , Proteína-Arginina N-Metiltransferasas/metabolismo , Recurrencia , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
6.
Nat Commun ; 10(1): 2723, 2019 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-31222014

RESUMEN

Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state. We show that inhibition of Lsd1 (Kdm1a) is able to overcome stable epigenetic resistance by facilitating the binding of the pioneer factor, Pu.1 and cofactor, Irf8, to nucleate new enhancers that regulate the expression of key survival genes. This enhancer switching results in the re-distribution of transcriptional co-activators, including Brd4, and provides the opportunity to disable their activity and overcome epigenetic resistance. Together these findings highlight key principles to help counteract non-genetic drug resistance.


Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Transactivadores/antagonistas & inhibidores , Animales , Antineoplásicos/uso terapéutico , Médula Ósea/patología , Sistemas CRISPR-Cas/genética , Línea Celular Tumoral , Epigénesis Genética/efectos de los fármacos , Femenino , Células HEK293 , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Ratones , Ratones Endogámicos C57BL , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Transactivadores/genética , Transactivadores/metabolismo , Transcripción Genética/efectos de los fármacos , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Nat Med ; 23(9): 1014-1015, 2017 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-28886001
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