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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.

Analysis of institutional authors

Lahera, AntonioCorresponding AuthorVela-Martin, LauraAuthorLopez-Lorenzo, Jose LAuthorSantos, JavierAuthorFernandez-Piqueras, JoseCorresponding AuthorVilla-Morales, MariaCorresponding Author

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August 4, 2024
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PIM1 is a potential therapeutic target for the leukemogenic effects mediated by JAK/STAT pathway mutations in T-ALL/LBL

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

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

Affiliations

Consorcio Invest Biomed Epidemiol & Salud Publ CIB, Madrid 28029, Spain - Author
Hosp Univ Fdn Jimenez Diaz, Div Hematol & Hemotherapy, Madrid 28040, Spain - Author
IIS Fdn Jimenez Diaz, Area Genet & Genom, Madrid 28040, Spain - Author
Inst Salud Carlos III, Unit Canc & Environm Epidemiol, Ctr Nacl Epidemiol, Madrid 28029, Spain - Author
Univ Autonoma Madrid CSIC UAM, Ctr Biol Mol Severo Ochoa CBM, Consejo Super Invest Cient, Dept Genome Dynam & Funct, Madrid 28049, Spain - Author
Univ Autonoma Madrid Madrid, Inst Mol Biol IUBM, Madrid 28049, Spain - Author
Univ Autonoma Madrid, Dept Biol, Madrid 28049, Spain - Author
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Abstract

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.

Keywords

Acute lymphoblastic-leukemiaC-mycCancerCell malignanciesGamma-secretase inhibitorsJak3Kinase inhibitorPhosphorylationSignaling pathwayTransformatio

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal NPJ Precis Oncol due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2024 there are still no calculated indicators, but in 2023, it was in position 43/322, thus managing to position itself as a Q1 (Primer Cuartil), in the category Oncology.

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-04:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 3.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 3 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 25.5.
  • The number of mentions on the social network X (formerly Twitter): 12 (Altmetric).
  • The number of mentions in news outlets: 2 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
  • Assignment of a Handle/URN as an identifier within the deposit in the Institutional Repository: https://repositorio.uam.es/handle/10486/717565

Leadership analysis of institutional authors

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (LAHERA ALONSO, ANTONIO) and Last Author (VILLA MORALES, MARIA DEL CONSUELO).

the authors responsible for correspondence tasks have been LAHERA ALONSO, ANTONIO, FERNANDEZ PIQUERAS, JOSE and VILLA MORALES, MARIA DEL CONSUELO.