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Anti-CD44 induces apoptosis in T lymphoma via mitochondrial depolarization

A blockade of CD44 can interfere with haematopoietic and leukemic stem cell homing, the latter being considered as a therapeutic option in haematological malignancies. We here aimed to explore the molecular mechanism underlying the therapeutic efficacy of anti-CD44. We noted that in irradiated mice...

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Bibliographic Details
Main Authors: Rajasagi, Mohini (Author) , von Au, Anja (Author) , Singh, Rahul (Author) , Hartmann, Natalie (Author) , Zöller, Margot (Author) , Marhaba, Rachid (Author)
Format: Article (Journal)
Language:English
Published: 26 July 2010
In: Journal of cellular and molecular medicine
Year: 2010, Volume: 14, Issue: 6b, Pages: 1453-1467
ISSN:1582-4934
DOI:10.1111/j.1582-4934.2009.00909.x
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1111/j.1582-4934.2009.00909.x
Verlag, lizenzpflichtig, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1582-4934.2009.00909.x
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Author Notes:Mohini Rajasagi, Anja von Au, Rahul Singh, Natalie Hartmann, Margot Zöller, Rachid Marhaba

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520 |a A blockade of CD44 can interfere with haematopoietic and leukemic stem cell homing, the latter being considered as a therapeutic option in haematological malignancies. We here aimed to explore the molecular mechanism underlying the therapeutic efficacy of anti-CD44. We noted that in irradiated mice reconstituted with a bone marrow cell transplant, anti-CD44 exerts a stronger effect on haematopoietic reconstitution than on T lymphoma (EL4) growth. Nonetheless, in the non-reconstituted mouse anti-CD44 suffices for a prolonged survival of EL4-bearing mice, where anti-CD44-prohibited homing actively drives EL4 cells into apoptosis. In vitro, a CD44 occupancy results in a 2-4-fold increase in apoptotic EL4 cells. Death receptor expression (CD95, TRAIL, TNFRI) remains unaltered and CD95 cross-linking-mediated apoptosis is not affected. Instead, CD44 ligation promotes mitochondrial depolarization that is accompanied by caspase-9 cleavage and is inhibited in the presence of a caspase-9 inhibitor. Apoptosis becomes initiated by activation of CD44-associated phosphatase 2A (PP2A) and proceeds via ERK1/2 dephosphorylation without ERK1/2 degradation. Accordingly, CD44-induced apoptosis could be mimicked by ERK1/2 inhibition, that also promotes EL4 cell apoptosis through the mitochondrial pathway. Thus, during haematopoietic stem cell reconstitution care should be taken not to interfere by a blockade of CD44 with haematopoiesis, which could be circumvented by selectively targeting leukemic CD44 isoforms. Beyond homing/settlement in the bone marrow niche, anti-CD44 drives leukemic T cells into apoptosis via the mitochondrial death pathway by CD44 associating with PP2A. Uncovering this new pathway of CD44-induced leukemic cell death provides new options of therapeutic interference. 
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