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The authors would like to thank Isabel Sastre and the Flow Cytometry Service of CBM for their support. This work was supported in part by funds from Ministerio de Economia y Competitividad (SAF2015-70561-R; MINECO/FEDER, EU to J.F.-P. and M.V.-M.); Ministerio de Ciencia, Innovacion y Universidades (RTI2018- 093330-B-I00; MCIU/FEDER, EU to J.F.-P. and J.S.); Fundacion Ramon Areces (CIVP19S7917 to J.F.-P.); Comunidad de Madrid (B2017/BMD-3778; LINFOMAS-CM to J.F.-P.); Asociacion Espanola Contra el Cancer (AECC, 2018; PROYE18054PIRI to J.F.-P.); and Instituto de Investigacion Sanitaria Fundacion Jimenez Diaz to J.F.-P.; institutional grants from the Fundacion Ramon Areces and Banco de Santander to the CBM are also acknowledged.DAS:Data from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative are managed by the National Cancer Institute (NCI) and accessible through the genotypes and phenotypes database (dbGaP, https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study). RNA-seq data from M07e cells expressing JAK3Q988P are available through the Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/geo/) under the accession number GSE266986. Additional data that support the findings of this study are available within the paper and its supplementary information.

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PIM1 is a potential therapeutic target for the leukemogenic effects mediated by JAK/STAT pathway mutations in T-ALL/LBL

Publicado en:NPJ Precis Oncol. 8 (1): 152- - 2024-07-20 8(1), DOI: 10.1038/s41698-024-00638-2

Autores: Lahera, Antonio; Vela-Martin, Laura; Fernandez-Navarro, Pablo; Llamas, Pilar; Lopez-Lorenzo, Jose L; Cornago, Javier; Santos, Javier; Fernandez-Piqueras, Jose; Villa-Morales, Maria

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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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