Phosphoproteomics Reveals the Role of Constitutive KAP1 Phosphorylation by B-cell Receptor Signaling in Chronic Lymphocytic Leukemia
Journal
Molecular cancer research : MCR
Journal Volume
20
Journal Issue
8
Pages
1222
Date Issued
2022
Author(s)
Wu, Jung-Lin
Hsin-Yi Wu
Tsai, Ho-Yang
Weng, Shao-Hsing
Lin, Kuen-Tyng
Zamanova, Margarita
Lee, Yi-Yuan
Angata, Takashi
Chen, Yu-Ju
Lin, Kuo-I
Abstract
Application of B-cell receptor (BCR) pathway inhibitor ibrutinib for chronic lymphocytic leukemia (CLL) is a major breakthrough, yet the downstream effects following inhibition of BCR signaling and during relapse await further clarification. By comparative phosphoproteomic profiling of B cells from patients with CLL and healthy donors, as well as CLL B cells collected at multiple time points during the course of ibrutinib treatment, we provided the landscape of dysregulated phosphoproteome in CLL and its dynamic alterations associated with ibrutinib treatment. Particularly, differential phosphorylation events associated with several signaling pathways, including BCR pathway, were enriched in patient CLL cells. A constitutively elevated phosphorylation level of KAP1 at serine 473 (S473) was found in the majority of CLL samples prior to treatment. Further verification showed that BCR activation promoted KAP1 S473 phosphorylation, whereas ibrutinib treatment abolished it. Depletion of KAP1 in primary CLL cells decelerated cell-cycle progression and ectopic expression of a KAP1 S473 phospho-mimicking mutant accelerated G2-M cell-cycle transition of CLL cells. Moreover, temporal phosphoproteomic profiles using a series of CLL cells isolated from one patient during the ibrutinib treatment revealed the dynamic changes of several molecules associated with BCR signaling in the ibrutinib responsive and recurrent stages.
Subjects
PREVIOUSLY UNTREATED PATIENTS; TYROSINE KINASE; IN-VITRO; RITUXIMAB; IBRUTINIB; CHEMOIMMUNOTHERAPY; CLL; CYCLOPHOSPHAMIDE; FLUDARABINE; COACTIVATOR
SDGs
Publisher
AMER ASSOC CANCER RESEARCH
Type
journal article