Phosphoproteomics Reveals the Role of Constitutive KAP1 Phosphorylation by B-cell Receptor Signaling in Chronic Lymphocytic Leukemia

Author:

Wu Jung-Lin12ORCID,Wu Hsin-Yi34ORCID,Wu Shang-Ju5,Tsai Ho-Yang126,Weng Shao-Hsing3ORCID,Lin Kuen-Tyng3,Lin Liang-In7,Yao Chi-Yuan5,Zamanova Margarita38ORCID,Lee Yi-Yuan1ORCID,Angata Takashi26ORCID,Tien Hwei-Fang5,Chen Yu-Ju3ORCID,Lin Kuo-I1ORCID

Affiliation:

1. 1Genomics Research Center, Academia Sinica, Taipei, Taiwan.

2. 2Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.

3. 3Institute of Chemistry, Academia Sinica, Taipei, Taiwan.

4. 4Instrumentation Center, National Taiwan University, Taipei, Taiwan.

5. 5Division of Hematology, Department of Internal Medicine, School of Medicine, National Taiwan University Hospital, Taipei, Taiwan.

6. 6Institute of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei, Taiwan.

7. 7Department of Clinical Laboratory Science and Medical Technology, College of Medicine, National Taiwan University, Taipei, Taiwan.

8. 8Sustainable Chemical Science and Technology, Taiwan International Graduate Program (TIGP), Academia Sinica, Taipei, Taiwan.

Abstract

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. Implications: This phosphoproteomic analysis and functional validation illuminated the phosphorylation of KAP1 at S473 as an important downstream BCR signaling event and a potential indicator for the success of ibrutinib treatment in CLL.

Funder

Academia Sinica

Ministry of Science and Technology

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology,Molecular Biology

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