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1.
Br J Haematol ; 201(4): 718-724, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36786170

RESUMO

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/LBL.


Assuntos
Leucemia-Linfoma de Células T do Adulto , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Janus Quinases/metabolismo , Transdução de Sinais , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Fatores de Transcrição STAT/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Linfócitos T/metabolismo
2.
Mol Cell Endocrinol ; 499: 110605, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31580897

RESUMO

The contribution of the pleiotropic hormone Prolactin (PRL) to several physiological and pathological processes is still unknown. To clarify the role of PRL in these processes during the last decade, different human PRL antagonists have been produced to either partially or fully block the wild type hormone activity. In this work, we have cloned these wild type and antagonist sequences in lentivectors (LV) to express them as recombinant self-processing polypeptides by employing a P2A sequence (hPRL-P2A-GFP). We show that these LVs can efficiently transduce and express the hPRL proteins in different cell types and that the P2A sequence does not affect their activities. Additionally, we have tested their activities in paracrine and autocrine cell culture experiments. Our results demonstrate that these recombinant hPRL-P2A proteins are bioactive in both paracrine and autocrine modes, highlighting the potential usefulness of these hPRL-containing LVs for determining the contribution of hPRL to different biological processes.


Assuntos
Lentivirus/genética , Prolactina/genética , Engenharia de Proteínas/métodos , Proteínas Recombinantes/metabolismo , Animais , Comunicação Autócrina , Técnicas de Cultura de Células , Linhagem Celular , Vetores Genéticos , Células HEK293 , Humanos , Comunicação Parácrina , Prolactina/metabolismo , Ratos
3.
Cancer Gene Ther ; 26(7-8): 216-233, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30622324

RESUMO

Interleukin 12 is a promising anti-cancer agent; however, IL12 systemic administration is hampered by side-effects. Although intratumoral administration of IL12 is giving promising results in clinical trials, only a small percentage of patients show a complete therapeutic response. This outcome could be improved by controlling the IL12 expression window. In this work we have tested the efficacy of a self-processing P2A and codon optimized murine IL12 (mIL12Pop) using inflammation-regulated lentivectors in a syngeneic tumor model. Our results show that implantation of cells expressing mIL12Pop employing either the strong constitutive SFFV promoter or a NFkB-based promoter reduced tumor growth, caused CD8+ T cell activation and increased IFNγ production. Importantly, the use of NFkBp-mIL12Pop increased the number of CD8+ TILs and improved the remission rate without increasing IL12-serum concentration. Further experiments suggest that there is a threshold intratumoral IL12 concentration that must be reached to trigger an efficient antitumor response and a limit that once surpassed causes detrimental systemic side effects. Altogether, these results demonstrate that using NFKBp-mIL12Pop significantly increases the overall survival of the mice. In summary, this new inflammation-regulated expression system might be useful for the development of new IL12 delivery systems with improved anti-tumor activity and limited toxicity.


Assuntos
Interleucina-12/uso terapêutico , NF-kappa B/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Interleucina-12/farmacologia , Masculino , Camundongos
4.
Rev. med. vet. zoot ; 65(1): 9-10, ene.-abr. 2018.
Artigo em Espanhol | LILACS | ID: biblio-961233
5.
Hum Gene Ther Methods ; 28(6): 340-351, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29160106

RESUMO

Vesicular stomatitis virus G glycoprotein (VSVg) is extensively used for retroviral and lentiviral vector (LV) pseudotyping. However, VSVg pseudotyped vectors are serum inactivated, blocking the in vivo gene delivery. Several strategies have been employed to prevent complement inactivation, including chemical and genetic envelope modifications. This study employed the streptococcal albumin-binding domain (ABD) to generate a construct to express ABD as a glycosylphosphatidylinositol-anchored protein. LV particles bearing ABD are able to bind bovine and human serum albumin in vitro. Neither the lentiviral vector production titer nor the in vitro transduction was affected by the ABD display. The study demonstrated that ABD-bearing LVs are protected from human complement inactivation. More importantly, intravenous administration demonstrated that the presence of ABD significantly reduces lentivector sequestration in liver and bone-marrow cells. Therefore, the use of ABD represents an improvement for in vivo gene therapy applications. The results strongly point to ABD display as a universal strategy to increase the in vivo efficacy of different viral vectors.


Assuntos
Proteínas de Bactérias/genética , Terapia Genética/métodos , Vetores Genéticos/genética , Glicoproteínas/genética , Vesiculovirus/genética , Proteínas do Envelope Viral/genética , Carga Viral , Albuminas/metabolismo , Animais , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Medula Óssea/metabolismo , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Glicoproteínas/química , Glicoproteínas/metabolismo , Células HEK293 , Humanos , Células Jurkat , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Domínios Proteicos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Vesiculovirus/metabolismo , Vesiculovirus/fisiologia , Proteínas do Envelope Viral/metabolismo
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