HSP90 inhibitors decrease AID levels and activity in mice and in human cells.
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.
Institut de Recherches Cliniques de Montréal, Montréal, Canada.
Damien
D
Montamat-Sicotte
Institut de Recherches Cliniques de Montréal, Montréal, Canada.|Department of Biochemistry, Université de Montréal, Montréal, QC, Canada.
Ludivine C
LC
Litzler
Research Laboratory on Chronic Lymphocytic Leukemia, Instituto Pasteur de Montevideo, Montevideo, Uruguay.
Cecilia
C
Abreu
Institut de Recherches Cliniques de Montréal, Montréal, Canada.|Department of Medicine, McGill University, Montréal, QC, Canada.
Shiva
S
Safavi
Institut de Recherches Cliniques de Montréal, Montréal, Canada.
Astrid
A
Zahn
Institut de Recherches Cliniques de Montréal, Montréal, Canada.
Alexandre
A
Orthwein
UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, USA.
Markus
M
Müschen
Research Laboratory on Chronic Lymphocytic Leukemia, Instituto Pasteur de Montevideo, Montevideo, Uruguay.
Pablo
P
Oppezzo
UCSF Benioff Children's Hospital and Research Institute at Oakland, Oakland, USA.
Denise P
DP
Muñoz
Institut de Recherches Cliniques de Montréal, Montréal, Canada.|Department of Biochemistry, Université de Montréal, Montréal, QC, Canada.|Department of Medicine, McGill University, Montréal, QC, Canada.|Department of Medicine and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, Canada.
Javier M
JM
Di Noia
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D003564:Cytidine Deaminase / Q000276:immunology*; D058750:Epithelial-Mesenchymal Transition / Q000276:immunology; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000276:immunology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000473:pathology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D018841:HSP90 Heat-Shock Proteins; D009363:Neoplasm Proteins; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
Activation induced deaminase (AID); Antibody response; Class switch recombination; HSP90 inhibitors; Leukemia