The JAK3Q988P mutation reveals oncogenic potential and resistance to ruxolitinib

T-cell acute lymphoblastic leukemia (T-ALL) arises from the malignant transformation of T-cell progenitors at various differentiation stages. Given that patients who relapse have a dismal prognosis, there is an urgent need to identify the molecular alterations that are present in such patients and promote leukemogenesis to implement personalized therapies with higher efficacy and fewer adverse effects. In the present manuscript, we identified the JAK3Q988P mutation in a T-ALL patient who did not achieve a durable response after the conventional treatment and whose tumor cells at relapse presented constitutive activation of the JAK/STAT pathway. Although JAK3Q988P has been previously identified in T-ALL patients from different studies, the functional consequences exerted by this mutation remain unexplored. Through the combination of different hematopoietic cellular models, we functionally characterize JAK3Q988P as an oncogenic mutation that contributes to leukemogenesis. Notably, JAK3Q988P not only promotes constitutive activation of the JAK/STAT pathway in the absence of cytokines and growth factors, as is the case for other JAK3 mutations that have been functionally characterized as oncogenic, but also functions independently of JAK1 and IL2RG, resulting in high oncogenic potential as well as resistance to ruxolitinib. Our results indicate that ruxolitinib may not be efficient for future patients bearing the JAK3Q988P mutation who instead may obtain greater benefits from treatments involving other pharmacological inhibitors such as tofacitinib.This work was supported in part by funds from Ministerio de Economía y Competitividad (SAF2015‐70561‐R; MINECO/FEDER, EU to J.F.‐P. and M.V.‐M.); Ministerio de Ciencia, Innovación y Universidades (RTI2018‐093330‐B‐I00; MCIU/FEDER, EU to J.F.‐P. and J.S.); Fundación Ramón Areces (CIVP19S7917 to J.F.‐P.); Comunidad de Madrid (B2017/BMD‐3778; LINFOMAS‐CM to J.F.‐P.); Asociación Española Contra el Cáncer (AECC, 2018; PROYE18054PIRI to J.F.‐P.);and Instituto de Investigación Sanitaria Fundación Jiménez Díaz to J.F.‐P.;institutional grants from the Fundación Ramón Areces and Banco de Santander to the CBMSO are also acknowledged.S

Comprehensive characterization of a novel, oncogenic and targetable SEPTIN6::ABL2 fusion in T-ALL

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SOCS3 deregulation contributes to aberrant activation of the JAK/STAT pathway in precursor T-cell neoplasms

Despite the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway being frequently altered in T-ALL/LBL, no specific therapy has been approved for T-ALL/LBL patients with constitutive signalling by JAK/STAT, so there is an urgent need to identify pathway members that may be potential therapeutic targets. In the present study, we searched for JAK/STAT pathway members potentially modulated through aberrant methylation and identified SOCS3 hypermethylation as a recurrent event in T-ALL/LBL. Additionally, we explored the implications of SOCS3 deregulation in T-ALL/LBL and demonstrated that SOCS3 counteracts the constitutive activation of the JAK/STAT pathway through different molecular mechanisms. Therefore, SOCS3 emerges as a potential therapeutic target in T-ALL/LBLComunidad de Madrid, Grant/Award Number: B2017/BMD-3778; LINFOMAS-CM; Fundación Científica Asociación Española Contra el Cáncer, Grant/Award Number: PROYE18054PIRI; Fundación Ramón Areces, Grant/Award Number: CIVP19S7917; Instituto de Investigación Sanitaria Fundación Jiménez Díaz; Ministerio de Ciencia, Innovación y Universidades, Grant/ Award Number: RTI2018- 093330-B-I00 and MCIU/FEDER; Ministerio de Economía y Competitividad, Grant/Award Number: SAF2015-70561-R and MINECO/FEDE

Aplicación de PC para interacción con central de detección de incendios

Ingeniería Técnica de Telecomunicación, especialidad Sonido e ImagenTelekomunikazio Ingeniaritza Teknikoa. Soinua eta Irudia Berezitasun

Simple fabrication of ultrahigh aspect ratio nanostructures for enhanced antireflectivity

In this work, the authors present a novel fabrication process to create periodic nanostructures with aspect ratio as high as 9.6. These nanostructures reduce spectral reflectance of silicon to less than 4% over the broad wavelength region from 200 to 2000 nm. At the visible range of the spectrum, from 200 to 650 nm, reflectivity is reduced to less than 0.1%. The aspect ratio and reflectance performance that the authors achieved have never been reported before for ordered tapered nanostructures, to our knowledge. © 2014 American Vacuum Society

Comprehensive characterization of a novel, oncogenic and targetable SEPTIN6::ABL2 fusion in T-ALL

Altres ajuts: Fundación Ramón Areces, CIVP19S7917; Comunidad de Madrid, B2017/BMD-3778; Asociación Española Contra el Cáncer, PROYE18054PIRI, LABAE20049RODR; Instituto de Investigación Sanitaria Fundación Jiménez Díaz; Fundación Ramón Areces; Banco de Santander