HSP90 inhibitors decrease AID levels and activity in mice and in human cells. Issue 8 (18th May 2015)

• Record Type: Journal Article
• Authors: Montamat‐Sicotte, Damien; Litzler, Ludivine C; Abreu, Cecilia; Safavi, Shiva; Zahn, Astrid; Orthwein, Alexandre; Müschen, Markus; Oppezzo, Pablo; Muñoz, Denise P; Di Noia, Javier M
• Is Part Of: European journal of immunology. Volume 45:Issue 8(2015:Aug.)
• Page Start: 2365
• Page End: 2376
• Publication Date: 2015-05-18
• Subjects: Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201545462
• Languages: English
• ISSNs: 0014-2980

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Activation induced deaminase (AID) initiates somatic hypermutation and class switch recombination of the Ig genes in antigen‐activated B cells, underpinning antibody affinity maturation and isotype switching. AID can also be pathogenic by contributing to autoimmune diseases and oncogenic mutations. Moreover, AID can exert noncanonical functions when aberrantly expressed in epithelial cells. The lack of specific inhibitors prevents therapeutic applications to modulate AID functions. Here, we have exploited our previous finding that the HSP90 molecular chaperoning pathway stabilizes AID in B cells, to test whether HSP90 inhibitors could target AID in vivo. We demonstrate that chronic administration of HSP90 inhibitors decreases AID protein levels and isotype switching in immunized mice. HSP90 inhibitors also reduce disease severity in a mouse model of acute B‐cell lymphoblastic leukemia in which AID accelerates disease progression. We further show that human AID protein levels are sensitive to HSP90 inhibition in normal and leukemic B cells, and that HSP90 inhibition prevents AID‐dependent epithelial to mesenchymal transition in a human breast cancer cell line in vitro. Thus, we provide proof‐of‐concept that HSP90 inhibitors indirectly target AID in vivo and that endogenous human AID is widely sensitive to them, which could have therapeutic applications.</p> </abstract>