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Analysis of institutional authors

Ondrisova, LauraAuthorMaiques-Diaz AAuthorCharalampopoulou, StellaAuthorMartin-Subero, Jose IAuthor

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February 27, 2025
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FoxO1/Rictor axis induces a nongenetic adaptation to ibrutinib via Akt activation in chronic lymphocytic leukemia

Publicated to: Journal Of Clinical Investigation. 134 (23): e173770- - 2024-12-02 134(23), DOI: 10.1172/JCI173770

Authors: Ondrisova, L; Seda, V; Hlavac, K; Pavelkova, P; Hoferkova, E; Chiodin, G; Kostalova, L; Pavlasova, GM; Filip, D; Vecera, J; Zeni, PF; Oppelt, J; Kahounova, Z; Vichova, R; Soucek, K; Panovska, A; Plevova, K; Pospisilova, S; Simkovic, M; Vrbacky, F; Lysak, D; Fernandes, SM; Davids, MS; Maiques-Diaz, A; Charalampopoulou, S; Martin-Subero, JI; Brown, JR; Doubek, M; Forconi, F; Mayer, J; Mraz, M

Affiliations

CEITEC Masaryk Univ, Mol Med, Brno, Czech Republic - Author
Charles Univ Prague, Fac Med Hradec Kralove, Prague, Czech Republic - Author
Czech Acad Sci, Inst Biophys, Dept Cytokinet, Brno, Czech Republic - Author
Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA - Author
Masaryk Univ, Fac Med, Brno, Czech Republic - Author
Univ Barcelona, Inst Invest Biomed August Pi I Sunyer IDIBAPS, Barcelona, Spain - Author
Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic - Author
Univ Hosp Hradec Kralove, Dept Internal Med Haematol 4, Prague, Czech Republic - Author
Univ Hosp Plzen, Dept Haematol & Oncol, Plzen, Czech Republic - Author
Univ Hosp Southampton NHS Trust, Canc Care Directorate, Haematol Dept, Southampton, England - Author
Univ Southampton, Fac Med, Canc Sci, Southampton, England - Author
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Abstract

Bruton tyrosine kinase (BTK) inhibitor therapy induces peripheral blood lymphocytosis in chronic lymphocytic leukemia (CLL), which lasts for several months. It remains unclear whether nongenetic adaptation mechanisms exist, allowing CLL cells' survival during BTK inhibitor-induced lymphocytosis and/or playing a role in therapy resistance. We show that in approximately 70% of CLL cases, ibrutinib treatment in vivo increases Akt activity above pretherapy levels within several weeks, leading to compensatory CLL cell survival and a more prominent lymphocytosis on therapy. Ibrutinib-induced Akt phosphorylation (pAktS473) is caused by the upregulation of Forkhead box protein O1 (FoxO1) transcription factor, which induces expression of Rictor, an assembly protein for the mTORC2 protein complex that directly phosphorylates Akt at serine 473 (S473). Knockout or inhibition of FoxO1 or Rictor led to a dramatic decrease in Akt phosphorylation and growth disadvantage for malignant B cells in the presence of ibrutinib (or PI3K inhibitor idelalisib) in vitro and in vivo. The FoxO1/ Rictor/pAktS473 axis represents an early nongenetic adaptation to B cell receptor (BCR) inhibitor therapy not requiring PI3K delta or BTK kinase activity. We further demonstrate that FoxO1 can be targeted therapeutically and its inhibition induces CLL cells' apoptosis alone or in combination with BTK inhibitors (ibrutinib, acalabrutinib, pirtobrutinib) and blocks their proliferation triggered by T cell factors (CD40L, IL-4, and IL-21).

Keywords

8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h) oneAcalabrutinibAdenineAgammaglobulinaemia tyrosine kinaseAnimalAnimal experimentAnimal modelAnimalsApoptosisArticleAzd 8055B cell chronic lymphocytic leukemiaB lymphocyteB lymphocyte receptorB-cell receptorBcr abl proteinBlk proteinBruton tyrosine kinaseBtkBtk protein, humanCd20 antibodyCd40 ligandCell line, tumorCell proliferationCell survivalChemokine receptor cxcr4Controlled studyDoublecortin like kinase 1Drug mechanismDrug therapyEnzyme inhibitionForkhead box protein o1Foxo1Foxo1 protein, humanGene activationGene knockoutGeneticsGerminal center kinaseHematologyHematopoietic cell kinaseHumanHuman cellHumansIbrutinibIdelalisibImmunoglobulin heavy chainIn vitro studyIn vivo studyIn-vitroInterleukin 21Interleukin 4Leukemia, lymphocytic, chronic, b-cellLeukemiasLymphocytosisMammalian target of rapamycin complex 1Mammalian target of rapamycin complex 2Messenger rnaMetabolismMiceMouseMutationsNeoplasm proteinsNima related kinase 1NonhumanOncogene protein v aktOncogene protein v rafOncologyPathologyPhosphatidylinositol 3 kinasePhosphorylatioPhosphorylationPiperidine derivativePiperidinesPirtobrutinibPlcg2 proteinPolo like kinase 1Protein expressionProtein kinase bProtein kinase lynProtein phosphorylationProtein tyrosine kinase cskProto-oncogene proteins c-aktPyrazole derivativePyrazolesPyrimidine derivativePyrimidinesRapamycin-insensitive companion of mtorRapamycin-insensitive companion of mtor proteinResistant cllSerine threonine protein kinase 3Serine threonine protein kinase ulk1Serine/threonine protein kinase wnk1Signal transductionT lymphocyteTargetsTranscriptionTranscription factor fkhrTreatment indicationTumor cell lineTumor proteinTyrosine kinase inhibitorUnclassified drugUpregulationVenetoclax

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Journal Of Clinical Investigation 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 5/195, thus managing to position itself as a Q1 (Primer Cuartil), in the category Medicine, Research & Experimental. Notably, the journal is positioned above the 90th percentile.

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2025-12-16:

  • WoS: 8
  • Scopus: 7

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 2025-12-16:

  • 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: 16.
  • 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: 17 (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: 15.
  • The number of mentions on the social network Facebook: 1 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 6 (Altmetric).
  • The number of mentions on Wikipedia: 1 (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.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Czech Republic; United Kingdom; United States of America.

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 (Bladé Creixenti, Joan) .