Kelch-like protein 6 (KLHL6)

Kelch-like protein 6 (KLHL6) is a member of the BTB-Kelch family of substrate adaptor proteins that assemble with Cullin-3 to form E3 ubiquitin ligase complexes, thereby targeting specific proteins for ubiquitin-mediated proteasomal degradation[1][2]. KLHL6 is predominantly expressed in germinal center B-cells, where it regulates B-cell receptor (BCR) signaling, B-cell maturation, and homeostasis[1]. KLHL6 mediates the degradation of proteins such as Roquin2 and BCR components (CD79A/CD79B), modulating pathways central to B-cell development and antigen response. Somatic mutations in KLHL6, frequently found in diffuse large B-cell lymphoma (DLBCL) and less commonly in chronic lymphocytic leukemia (CLL), impair its function, resulting in aberrant BCR signaling and activation of oncogenic lymphocyte pathways (notably the NF-κB pathway)[1][2]. KLHL6 loss or mutation has been mechanistically linked to increased DLBCL growth and poorer outcomes, and may serve as a resistance marker to BCR pathway-targeting agents (e.g., ibrutinib) and other therapies such as MLN4924 or bortezomib[2]. KLHL6 mutations thus define a functionally distinct molecular subset of B-cell lymphomas with targetable vulnerabilities.

Other names

KLHL6kelch-like family member 6Kelch-like protein KLHL6FLJ00029

Indirect: Targeting the downstream signaling events and feedback loops affected by KLHL6 loss, such as NF-κB activation, via BCR signaling inhibitors and proteasome inhibitors[2].