PIM1 is a potential therapeutic target for the leukemogenic effects mediated by JAK/STAT pathway mutations in T-ALL/LBL
Precursor T-cell neoplasms (T-ALL/LBL) are aggressive hematological malignancies that arise from the malignant transformation of immature thymocytes. Despite the JAK/STAT pathway is recurrently altered in these neoplasms, there are not pharmacological inhibitors officially approved for the treatment...
| Autores: | , , , , , , , , |
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| Tipo de documento: | artigo |
| Data de publicação: | 2024 |
| País: | España |
| Recursos: | Universidad Autónoma de Madrid |
| Repositório: | Biblos-e Archivo. Repositorio Institucional de la UAM |
| Idioma: | inglês |
| OAI Identifier: | oai:repositorio.uam.es:10486/717565 |
| Acesso em linha: | http://hdl.handle.net/10486/717565 https://dx.doi.org/10.1038/s41698-024-00638-2 |
| Access Level: | Acceso aberto |
| Palavra-chave: | Antileukemic agent janus kinase mammalian target of rapamycin messenger RNA myc protein pim 447 protein kinase Pim 1 STAT protein unclassified drug Biología y Biomedicina / Biología |
| Resumo: | Precursor T-cell neoplasms (T-ALL/LBL) are aggressive hematological malignancies that arise from the malignant transformation of immature thymocytes. Despite the JAK/STAT pathway is recurrently altered in these neoplasms, there are not pharmacological inhibitors officially approved for the treatment of T-ALL/LBL patients that present oncogenic JAK/STAT pathway mutations. In the effort to identify potential therapeutic targets for those patients, we followed an alternative approach and focused on their transcriptional profile. We combined the analysis of molecular data from T-ALL/LBL patients with the generation of hematopoietic cellular models to reveal that JAK/STAT pathway mutations are associated with an aberrant transcriptional profile. Specifically, we demonstrate that JAK/STAT pathway mutations induce the overexpression of the PIM1 gene. Moreover, we show that the pan-PIM inhibitor, PIM447, significantly reduces the leukemogenesis, as well as the aberrant activation of c-MYC and mTOR pathways in cells expressing different JAK/STAT pathway mutations, becoming a potential therapeutic opportunity for a relevant subset of T-ALL/LBL patients |
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