Referencia

PortadaCancerDiscoveryCancer Discov; 2015 Dec;5(12):1328-43. doi: 10.1158/2159-8290.CD-15-0892.

Autores

Alberto Martín-Lorenzo, Julia Hauer, Carolina Vicente-Dueñas, Franziska Auer, Inés González-Herrero, Idoia García-Ramírez, Sebastian Ginzel, Ralf Thiele, Stefan N. Constantinescu, Christoph Bartenhagen, Martin Dugas, Michael Gombert , Daniel Schäfer, Oscar Blanco, Andrea Mayado, Alberto Orfao, Diego Alonso-López, Javier De Las Rivas, César Cobaleda, María Begoña García-Cenador, Francisco Javier García-Criado, Isidro Sánchez-García, and Arndt Borkhardt.

Resumen

Earlier in the past century, infections were regarded as the most likely cause of childhood B-cell precursor acute lymphoblastic leukemia (pB-ALL). However, there is a lack of relevant biologic evidence supporting this hypothesis. We present in vivo genetic evidence mechanistically connecting inherited susceptibility to pB-ALL and postnatal infections by showing that pB-ALL was initiated in Pax5 heterozygous mice only when they were exposed to common pathogens. Strikingly, these murine pB-ALLs closely resemble the human disease. Tumor exome sequencing revealed activating somatic, nonsynonymous mutations of Jak3 as a second hit. Transplantation experiments and deep sequencing suggest that inactivating mutations in Pax5 promote leukemogenesis by creating an aberrant progenitor compartment that is susceptible to malignant transformation through accumulation of secondary Jak3 mutations. Thus, treatment of Pax5+/− leukemic cells with specificJAK1/3 inhibitors resulted in increased apoptosis. These results uncover the causal role of infection in pB-ALL development.

Descripción

Las infecciones fueron propuestas como causa del desarrollo de pB-ALL por primera en 1917 por G. Ward. Sin embargo, hasta la fecha no existían evidencias científicas que soportaran esta hipótesis. Los resultados publicados en Cancer Discovery, demuestran por primera vez que la exposición a infección causa leucemia en ratones con una susceptibilidad genética heredada, mostrando que el desarrollo de pB-ALL se produce en ratones Pax5+/- solamente cuando son expuestos a infección.

 

Fotogrupofeb

 

REFERENCIA DEL GRUPO INVESTIGADOR

Este trabajo es el fruto de la colaboración internacional entre los grupos dirigidos por Prof. Arndt Borkhardt en Dusseldorf (Heinrich-Heine University Dusseldorf, Germany) e Isidro Sánchez-García en Salamanca (IBMCC-CIC). Esta investigación demuestra por primera vez cómo la infección causa leucemia.

Descárgate este artículo aquí.

¿Acabas de publicar un artículo interesante?

Manda la referencia a través de nuestro formulario.  Límite de edad 32 años. Los artículos seleccionados serán destacados como artículos del mes y participarán en el Premio al mejor artículo de jóvenes de la SEBBM, que se entregará en el congreso de la SEBBM (inscripción y alojamiento gratuitos).

Otros "Artículos del mes"

Structure–Function of MamC Loop and Its Effect on the *in Vitro* Precipitation of Biomimetic Magnetite Nanoparticles

01-09-2019

MamC, an integral protein of the magnetosome membrane, has recently been proposed as a strong candidate to produce biomimetic (magnetosome-like) magnetite nanoparticles that could be used as an alternative to...

Leer más

Sticholysin, Sphingomyelin, and Cholesterol: A Closer Look at a Tripartite Interaction

01-08-2019

Actinoporins are a group of soluble toxic proteins that bind to membranes containing sphingomyelin (SM) and oli- gomerize to form pores. Sticholysin II (StnII) is a member of the actinoporin...

Leer más

Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour

01-07-2019

To satisfy its high energetic demand, the brain depends on the metabolic cooperation of various cell types. For example, astrocytic-derived lactate sustains memory consolidation by serving both as an oxidizable...

Leer más

Glucose restriction promotes osteocyte specification by activating a PGC-1α-dependent transcriptional program

03-06-2019

Osteocytes, the most abundant of bone cells, differentiate while they remain buried within the bone matrix. This encasement limits their access to nutrients and likely affects their differentiation, a process...

Leer más

ParB dynamics and the critical role of the CTD in DNA condensation unveiled by combined force-fluorescence measurements

01-05-2019

/Bacillus subtilis/ ParB forms multimeric networks involving non-specific DNA binding leading to DNA condensation. Previously, we found that an excess of the free C-terminal domain (CTD) of ParB impeded DNA...

Leer más

Therapeutic targeting of HER2-CB2R heteromers in HER2-positive breast cancer

01-04-2019

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New...

Leer más

p73 regulates ependymal planar cell polarity by modulating actin and microtubule cytoskeleton

01-03-2019

Planar cell polarity (PCP) and intercellular junctional complexes establish tissue structure and coordinated behaviors across epithelial sheets. In multiciliated ependymal cells, rotational and translational PCP coordinate cilia beating and direct...

Leer más

β‐RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9R239X mice

01-02-2019

Coenzyme Q (CoQ) deficiency has been associated with primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In...

Leer más

Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons

02-01-2019

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of...

Leer más

Dynamic acetylation of cytosolic phosphoenolpyruvate carboxykinase toggles enzyme activity between gluconeogenic and anaplerotic reactions

01-12-2018

Cytosolic phosphoenolpyruvate carboxykinase (PCK1) is considered a gluconeogenic enzyme; however, its metabolic functions and regulatory mechanisms beyond gluconeogenesis are poorly understood. Here, we describe that dynamic acetylation of PCK1 interconverts...

Leer más

Socios Protectores