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Analysis of institutional authors

Rosich, LAuthorSaborit-Villarroya, IAuthorLopez-Guerra, MAuthorXargay-Torrent, SAuthorMontraveta, AAuthorAymerich, MAuthorVillamor, NAuthorCampo, EAuthorPerez-Galan, PAuthorRoue, GAuthorColomer, DCorresponding Author

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May 5, 2014
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The phosphatidylinositol-3-kinase inhibitor NVP-BKM120 overcomes resistance signals derived from microenvironment by regulating the Akt/FoxO3a/Bim axis in chronic lymphocytic leukemia cells

Publicated to: Haematologica. 98 (11): 1739-1747 - 2013-11-01 98(11), DOI: 10.3324/haematol.2013.088849

Authors:

Rosich, Laia; Saborit-Villarroya, Ifigenia; Lopez-Guerra, Monica; Xargay-Torrent, Silvia; Montraveta, Arnau; Aymerich, Marta; Villamor, Neus; Campo, Elias; Perez-Galan, Patricia; Roue, Gael; Colomer, Dolors
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Affiliations

Univ Barcelona, Hosp Clin, Inst Invest Biomed August Pi Sunyer IDIBAPS, Hematopathol Unit, Barcelona, Spain - Author

Abstract

Phosphatidylinositol-3-kinase pathway is constitutively activated in chronic lymphocytic leukemia mainly due to microenvironment signals, including stromal cell interaction and CXCR4 and B-cell receptor activation. Because of the importance of phosphatidylinositol-3-kinase signaling in chronic lymphocytic leukemia, we investigated the activity of the NVP-BKM120, an orally available pan class I phosphatidylinositol-3-kinase inhibitor. Sensitivity to NVP-BKM120 was analyzed in chronic lymphocytic leukemia primary samples in the context of B-cell receptor and microenvironment stimulation. NVP-BKM120 promoted mitochondrial apoptosis in most primary cells independently of common prognostic markers. NVP-BKM120 activity induced the blockage of phosphatidylinositol-3-kinase signaling, decreased Akt and FoxO3a phosphorylation leading to concomitant Mcl-1 downregulation and Bim induction. Accordingly, selective knockdown of BIM rescued cells from NVP-BKM120-induced apoptosis, while the kinase inhibitor synergistically enhanced the apoptosis induced by the BH3-mimetic ABT-263. We also found NVP-BKM120 to inhibit B-cell receptor- and stroma-dependent Akt pathway activation, thus sensitizing chronic lymphocytic leukemia cells to bendamustine and fludarabine. Furthermore, NVP-BKM120 down-regulated secretion of chemokines after B-cell receptor stimulation and inhibited cell chemotaxis and actin polymerization upon CXCR4 triggering by CXCL12. Our findings establish that NVP-BKM120 effectively inhibits the phosphatidylinositol-3-kinase signaling pathway and disturbs the protective effect of the tumor microenvironment with the subsequent apoptosis induction through the Akt/FoxO3a/Bim axis. We provide here a strong rationale for undertaking clinical trials of NVP-BKM120 in chronic lymphocytic leukemia patients alone or in combination therapies.
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Keywords

AgedAged, 80 and overAminopyridinesApoptosis regulatory proteinsAutopsyBcl-2-like protein 11Bcl2l11 protein, humanCancerCell movementCoculture techniquesDeathDementiaDrug resistance, neoplasmDysfunctionEtiologyExpressionForkhead box protein o3Forkhead transcription factorsFoxo3 protein, humanGuidelinesHumansLeukemia, lymphocytic, chronic, b-cellMembrane proteinsMiddle agedMorpholinesNvp-bkm120Oncogene protein v-aktPhosphatidylinositol 3-kinasesPhosphoinositide-3 kinase inhibitorsProto-oncogene proteinsTumor microenvironment

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Haematologica 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, 2013, it was in position 5/68, thus managing to position itself as a Q1 (Primer Cuartil), in the category Hematology.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations from Scopus Elsevier, it yields a value for the Field-Weighted Citation Impact from the Scopus agency: 1.02, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 13, 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-12-22, the following number of citations:

  • WoS: 40
  • Scopus: 40
  • Europe PMC: 31
  • Google Scholar: 56
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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 2025-12-22:

  • 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: 30 (PlumX).

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.
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Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: PAVIA.

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 (Rosich Moya, Laia) and Last Author (Colomer Pujol, Dolors).

the author responsible for correspondence tasks has been Colomer Pujol, Dolors.

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