Targeting the NTSR2/TrkB oncogenic pathway in chronic lymphocytic leukemia

Current therapies that target the B-cell receptor pathway or the inhibition of anti-apoptotic proteins do not prevent the progressive forms of chronic lymphocytic leukemia (CLL), have low long-term efficacy and are subject to therapeutic resistance. Deciphering the mechanisms of leukemic cell surviv...

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Published inScientific reports Vol. 14; no. 1; pp. 6084 - 13
Main Authors Ikhlef, Léa, Yassine, May, Chandouri, Boutaîna, Rivière, Léa, Naves, Thomas, Dmytruk, Natalya, Gachard, Nathalie, Jauberteau, Marie-Odile, Gallet, Paul-François
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 13.03.2024
Nature Publishing Group
Nature Portfolio
Subjects
631/154/555
631/67/1990/283/1895
Apoptosis
B-cell receptor
Cell survival
Chronic lymphocytic leukemia
Cytotoxicity
Humanities and Social Sciences
Kinases
Leukemia
Lymphocytes B
multidisciplinary
Neurotensin
Peptides
Proteins
Science
Science (multidisciplinary)
TrkB receptors
Tropomyosin
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Summary:Current therapies that target the B-cell receptor pathway or the inhibition of anti-apoptotic proteins do not prevent the progressive forms of chronic lymphocytic leukemia (CLL), have low long-term efficacy and are subject to therapeutic resistance. Deciphering the mechanisms of leukemic cell survival and searching for new specific targets therefore remain major challenges to improve the management of this disease. It was evidenced that NTSR2 (neurotensin receptor 2), through the recruitment of TRKB (tropomyosin related kinase B), induces survival pathways in leukemic B cells. We have investigated the therapeutic potential of this protein complex as a new target. The binding domain of NTSR2 and TRKB was identified and a peptide targeting the latter was designed. The peptide binds TRKB and efficiently decreases the interaction of the two proteins. It is also effectively internalized by CLL-B cells in which it notably affects Src family kinase signaling and anti-apoptotic proteins levels. It demonstrated a cytotoxic effect both in vitro on the MEC-1 cell line and ex vivo on a cohort of 30 CLL patients. Altogether, these results underline the therapeutic potential of the NTSR2/TRKB protein complex as a target in CLL and open new perspectives for the development of targeted therapies.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-024-56663-5