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"

Sarcoplasmic reticulum Ca2+ decreases with age and correlates with the decline in muscle function in Drosophila

29-05-2020

Sarcopenia, the loss of muscle mass and strength associated with age, has been linked to impairment of the cytosolic Ca2+ peak that triggers muscle contraction, but mechanistic details remain unknown...

Leer más

Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase

30-04-2020

Core-fucosylation is an essential biological modification by which a fucose is transferred from GDP-β-L-fucose to the innermost N-acetylglucosamine residue of N-linked glycans. A single human enzyme α1,6-fucosyltransferase (FUT8) is the...

Leer más

Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3

31-03-2020

Polypeptide GalNAc-transferase T3 (GalNAc-T3) regulates fibroblast growth factor 23 (FGF23) by O-glycosylating Thr178 in a furin proprotein processing motif RHT 178R ↓S. FGF23 regulates phosphate homeostasis and deficiency in GALNT3...

Leer más

Identification of distinct maturation steps involved in human 40S ribosomal subunit biosynthesis

29-02-2020

Technical problems intrinsic to the purification of preribosome intermediates have limited our understanding of ribosome biosynthesis in humans. Addressing this issue is important given the implication of this biological process...

Leer más

Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis

23-01-2020

B-cell acute lymphoblastic leukemia is the commonest childhood cancer. In infants, B-cell acute lymphoblastic leukemia remains fatal, especially in patients with t(4;11), present in ~80% of cases. The pathogenesis of...

Leer más

Mip6 binds directly to the Mex67 UBA domain to maintain low levels of Msn2/4 stress-dependent mRNAs

23-12-2019

RNA-binding proteins (RBPs) participate in all steps of gene expression, underscoring their potential as regulators of RNA homeostasis. We structurally and functionally characterize Mip6, a four-RNA recognition motif (RRM)-containing RBP...

Leer más

A bacterial light response reveals an orphan desaturase for human plasmalogen synthesis

01-12-2019

Plasmalogens are glycerophospholipids with a hallmark sn-1 vinyl ether bond. These lipids are found in animals and some bacteria and have proposed membrane organization, signaling, and antioxidant roles. We discovered...

Leer más

The structure of a polygamous repressor reveals how phage-inducible chromosomal islands spread in nature

01-11-2019

Stl is a master repressor encoded by Staphylococcus aureus pathogenicity islands (SaPIs) that maintains integration of these elements in the bacterial chromosome. After infection or induction of a resident helper...

Leer más

Self-Assembling ELR-Based Nanoparticles as Smart Drug-Delivery Systems Modulating Cellular Growth via Akt

01-10-2019

This work investigates the physicochemical properties and in vitro accuracy of a genetically engineered drug delivery system based on elastin-like block recombinamers. The DNA recombinant technics allowed us to create...

Leer más

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

Socios Protectores