Response to Bruton's tyrosine kinase inhibitors in aggressive lymphomas linked to chronic selective autophagy.
Cancer Cell
; 42(2): 238-252.e9, 2024 02 12.
Article
em En
| MEDLINE
| ID: mdl-38215749
ABSTRACT
Diffuse large B cell lymphoma (DLBCL) is an aggressive, profoundly heterogeneous cancer, presenting a challenge for precision medicine. Bruton's tyrosine kinase (BTK) inhibitors block B cell receptor (BCR) signaling and are particularly effective in certain molecular subtypes of DLBCL that rely on chronic active BCR signaling to promote oncogenic NF-κB. The MCD genetic subtype, which often acquires mutations in the BCR subunit, CD79B, and in the innate immune adapter, MYD88L265P, typically resists chemotherapy but responds exceptionally to BTK inhibitors. However, the underlying mechanisms of response to BTK inhibitors are poorly understood. Herein, we find a non-canonical form of chronic selective autophagy in MCD DLBCL that targets ubiquitinated MYD88L265P for degradation in a TBK1-dependent manner. MCD tumors acquire genetic and epigenetic alterations that attenuate this autophagic tumor suppressive pathway. In contrast, BTK inhibitors promote autophagic degradation of MYD88L265P, thus explaining their exceptional clinical benefit in MCD DLBCL.
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Base de dados:
MEDLINE
Assunto principal:
Linfoma Difuso de Grandes Células B
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article