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1.
Nature ; 616(7958): 755-763, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37046083

RESUMEN

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.


Asunto(s)
Hematopoyesis Clonal , Células Madre Hematopoyéticas , Animales , Humanos , Ratones , Alelos , Hematopoyesis Clonal/genética , Estudio de Asociación del Genoma Completo , Hematopoyesis/genética , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Mutación , Regiones Promotoras Genéticas
2.
Circ Res ; 130(10): 1510-1530, 2022 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-35430876

RESUMEN

BACKGROUND: Coronary artery disease is an incurable, life-threatening disease that was once considered primarily a disorder of lipid deposition. Coronary artery disease is now also characterized by chronic inflammation' notable for the buildup of atherosclerotic plaques containing immune cells in various states of activation and differentiation. Understanding how these immune cells contribute to disease progression may lead to the development of novel therapeutic strategies. METHODS: We used single-cell technology and in vitro assays to interrogate the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity. RESULTS: In addition to macrophages, we found a high proportion of αß T cells in the coronary plaques. Most of these T cells lack high expression of CCR7 and L-selectin, indicating that they are primarily antigen-experienced memory cells. Notably, nearly one-third of these cells express the HLA-DRA surface marker, signifying activation through their TCRs (T-cell receptors). Consistent with this, TCR repertoire analysis confirmed the presence of activated αß T cells (CD4

Asunto(s)
Enfermedad de la Arteria Coronaria , Placa Aterosclerótica , Linfocitos T , Antígenos , Células Clonales/inmunología , Enfermedad de la Arteria Coronaria/inmunología , Células Endoteliales , Epítopos , Cadenas alfa de HLA-DR , Humanos , Activación de Linfocitos , Placa Aterosclerótica/inmunología , Linfocitos T/inmunología
3.
Nat Cardiovasc Res ; 2(9): 805-818, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39196062

RESUMEN

Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence of a cancer-associated somatic mutation in white blood cells in the absence of overt hematological malignancy. It arises most commonly from loss-of-function mutations in the epigenetic regulators DNMT3A and TET2. CHIP predisposes to both hematological malignancies and atherosclerotic cardiovascular disease in humans. Here we demonstrate that loss of Dnmt3a in myeloid cells increased murine atherosclerosis to a similar degree as previously seen with loss of Tet2. Loss of Dnmt3a enhanced inflammation in macrophages in vitro and generated a distinct adventitial macrophage population in vivo which merges a resident macrophage profile with an inflammatory cytokine signature. These changes surprisingly phenocopy the effect of loss of Tet2. Our results identify a common pathway promoting heightened innate immune cell activation with loss of either gene, providing a biological basis for the excess atherosclerotic disease burden in carriers of these two most prevalent CHIP mutations.


Asunto(s)
Aterosclerosis , ADN (Citosina-5-)-Metiltransferasas , ADN Metiltransferasa 3A , Proteínas de Unión al ADN , Dioxigenasas , Modelos Animales de Enfermedad , Mutación con Pérdida de Función , Macrófagos , Fenotipo , Proteínas Proto-Oncogénicas , Animales , Femenino , Masculino , Ratones , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Aterosclerosis/genética , Aterosclerosis/patología , Aterosclerosis/inmunología , Hematopoyesis Clonal/genética , Citocinas/metabolismo , Citocinas/genética , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN Metiltransferasa 3A/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Inmunidad Innata/genética , Mediadores de Inflamación/metabolismo , Macrófagos/metabolismo , Macrófagos/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Proto-Oncogénicas/genética
4.
Cell Stem Cell ; 28(8): 1335-1336, 2021 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-34358435

RESUMEN

In this issue of Cell Stem Cell, Hormaechea-Agulla et al. (2021) demonstrate that IFNγ signaling following an infection in mice provides a selective pressure that drives growth of Dnmt3a-/- hematopoietic stem cells. This clonal expansion is mediated by global methylation changes that lead to an increased self-renewing capacity.


Asunto(s)
ADN (Citosina-5-)-Metiltransferasas , Células Madre Hematopoyéticas , Animales , Ratones
5.
Curr Opin Genet Dev ; 66: 63-69, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33422951

RESUMEN

In the multi-hit model of carcinogenesis, a precancerous state often precedes overt malignancy. Identification of these states has been of great interest as they allow for early identification of at-risk individuals before the appearance of a future cancer. One such condition has recently been described for blood cancers: Clonal Hematopoiesis of Indeterminate Potential (CHIP). Recent research advances have elucidated the risk of progression of CHIP to myeloid malignancies, its potential as a precursor for non-myeloid blood cancers, and its association with non-hematological cancers. Understanding the evolution of CHIP to hematological malignancy may help identify CHIP carriers at high risk of transformation and lead to the development of targeted therapies that can be deployed preemptively.


Asunto(s)
Carcinogénesis/genética , Hematopoyesis Clonal/genética , Neoplasias Hematológicas/genética , Neoplasias/genética , Neoplasias Hematológicas/patología , Humanos , Mutación/genética , Neoplasias/patología
6.
Aging (Albany NY) ; 9(9): 1957-1970, 2017 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-28904242

RESUMEN

The G-quadruplex is a non-canonical DNA secondary structure formed by four DNA strands containing multiple runs of guanines. G-quadruplexes play important roles in DNA recombination, replication, telomere maintenance, and regulation of transcription. Small molecules that stabilize the G-quadruplexes alter gene expression in cancer cells. Here, we hypothesized that the G-quadruplexes regulate transcription in neurons. We discovered that pyridostatin, a small molecule that specifically stabilizes G-quadruplex DNA complexes, induced neurotoxicity and promoted the formation of DNA double-strand breaks (DSBs) in cultured neurons. We also found that pyridostatin downregulated transcription of the Brca1 gene, a gene that is critical for DSB repair. Importantly, in an in vitro gel shift assay, we discovered that an antibody specific to the G-quadruplex structure binds to a synthetic oligonucleotide, which corresponds to the first putative G-quadruplex in the Brca1 gene promoter. Our results suggest that the G-quadruplex complexes regulate transcription in neurons. Studying the G-quadruplexes could represent a new avenue for neurodegeneration and brain aging research.


Asunto(s)
Aminoquinolinas/farmacología , Proteína BRCA1/biosíntesis , Daño del ADN/efectos de los fármacos , Neuronas/efectos de los fármacos , Ácidos Picolínicos/farmacología , Transcripción Genética/efectos de los fármacos , Animales , Regulación hacia Abajo , G-Cuádruplex/efectos de los fármacos , Regulación de la Expresión Génica , Ratas
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