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Maiques-Diaz AAuthorMartin-Subero, Jose IAuthor
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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, Laura; Seda, Vaclav; Hlavac, Krystof; Pavelkova, Petra; Hoferkova, Eva; Chiodin, Giorgia; Kostalova, Lenka; Pavlasova, Gabriela Mladonicka; Filip, Daniel; Vecera, Josef; Zeni, Pedro Faria; Oppelt, Jan; Kahounova, Zuzana; Vichova, Rachel; Soucek, Karel; Panovska, Anna; Plevova, Karla; Pospisilova, Sarka; Simkovic, Martin; Lysak, Daniel; Fernandes, Stacey M; Davids, Matthew S; Charalampopoulou, Stella; Martin-Subero, Jose I; Brown, Jennifer R; Doubek, Michael; Forconi, Francesco; Mayer, Jiri; Mraz, Marek

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
AdenineAgammaglobulinaemia tyrosine kinaseAnimalsB-cell receptorBtkBtk protein, humanCell line, tumorDrug therapyForkhead box protein o1Foxo1Foxo1 protein, humanHematologyHumansIbrutinibIn-vitroLeukemia, lymphocytic, chronic, b-cellLeukemiasMiceMutationsNeoplasm proteinsOncologyPhosphorylatioPhosphorylationPiperidinesProto-oncogene proteins c-aktPyrazolesPyrimidinesRapamycin-insensitive companion of mtor proteinResistant cllSignal transductionTargetsTranscriptionTyrosine kinase inhibitor

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 4/189, 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 2025-04-30:

  • WoS: 2
  • Scopus: 3
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 2025-04-30:

  • 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: 11.
  • 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: 11 (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: 12.18.
  • The number of mentions on the social network Facebook: 1 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 7 (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.