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Cited by 807Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentAcute Lymphoblastic Leukemia research

Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765

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Herman, Sarah E. M., Gordon, Amber L., Hertlein, Erin, Ramanunni, Asha, Zhang, Xiaoli, Jaglowski, Samantha, Flynn, Joseph, Jones, Jeffrey +5 more·2011·Blood
DOI 10.1182/blood-2011-01-328484PMC PMC3122947
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Abstract

B-cell receptor (BCR) signaling is aberrantly activated in chronic lymphocytic leukemia (CLL). Bruton tyrosine kinase (BTK) is essential to BCR signaling and in knockout mouse models its mutation has a relatively B cell–specific phenotype. Herein, we demonstrate that BTK protein and mRNA are significantly over expressed in CLL compared with normal B cells. Although BTK is not always constitutively active in CLL cells, BCR or CD40 signaling is accompanied by effective activation of this pathway. Using the irreversible BTK inhibitor PCI-32765, we demonstrate modest apoptosis in CLL cells that is greater than that observed in normal B cells. No influence of PCI-32765 on T-cell survival is observed. Treatment of CD40 or BCR activated CLL cells with PCI-32765 results in inhibition of BTK tyrosine phosphorylation and also effectively abrogates downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. In addition, PCI-32765 inhibits activation-induced proliferation of CLL cells in vitro, and effectively blocks survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement, and stromal cell contact. Based on these collective data, future efforts targeting BTK with the irreversible inhibitor PCI-32765 in clinical trials of CLL patients is warranted.

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  • Ibrutinib is an irreversible inhibitor of BTK.

    “Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL).”

    From Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib (2014) · cites this paper as [6]

    The section on PCI-32765-induced cytotoxicity states that PCI-32765 is an irreversible BTK inhibitor. Our copy does not name ibrutinib or establish that it is the same compound, so it does not fully support the claim as worded. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Ibrutinib irreversibly binds BTK at the C481 residue.

    “Ibrutinib irreversibly binds BTK at the C481 residue, rendering it kinase-inactive”

    From Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib (2014) · cites this paper as [6]

    The Introduction and Discussion describe PCI-32765 as an irreversible BTK inhibitor, and the section on BCR-dependent signaling reports reduced BTK phosphorylation consistent with inhibited kinase activity. Our copy does not identify PCI-32765 as ibrutinib or state that it binds BTK at C481, so those specifics are not established by this source. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Herman, S. E. M., Gordon, A. L., Hertlein, E., Ramanunni, A., Zhang, X., Jaglowski, S., Flynn, J., Jones, J., Blum, K. A., Buggy, J. J., Hamdy, A., Johnson, A. J., & Byrd, J. C.
Affiliations
  • The Ohio State University Wexner Medical Center (US)
  • Division of Hematology, Department of Internal Medicine and
  • The Ohio State University (US)
  • Pharmacyclics (United States) (US)
Corresponding author
  • Johnson, Amy J.
  • Byrd, John C.
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2011-06-09
Volume
117
Issue
23
Pages
6287-6296
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2011-01-328484
PMC
PMC3122947
OpenAlex
W2075875145
Cited by
807
References
0
Citations by year
2026: 17 · 2025: 28 · 2024: 43 · 2023: 31 · 2022: 38 · 2021: 52 · 2020: 56 · 2019: 52 · 2018: 56 · 2017: 64 · 2016: 67 · 2015: 83 · 2014: 85 · 2013: 73 · 2012: 50
FWCI
35.71
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • D. Warren Brown Family Foundation
  • National Institutes of Health (4p01ca081534-16)
  • National Cancer Institute (P01CA095426, P50CA140158, P01 CA81534, P01CA95426, P30CA016058, K12CA133250, P01-CA-081534)
Topics
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
Keywords
Bruton's tyrosine kinase, chronic lymphocytic leukemia, B cell receptor signaling, CD40 signaling, BTK inhibitors, apoptosis, ERK1/2, phosphatidylinositol 3-kinase, NF-κB, tumor microenvironment, fibronectin, CD40 ligand, BAFF, interleukin-6, IL-4, TNF-α
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Adenine, Animals, B-Lymphocytes, Cell Survival, Drug Screening Assays, Antitumor, Female, Humans, Male, Neoplasm Proteins, Piperidines, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Receptors, Antigen, B-Cell, T-Lymphocytes, Tumor Necrosis Factor-alpha, Leukemia, Lymphocytic, Chronic, B-Cell, Interleukin-4, Interleukin-6, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Leukemic, NF-kappa B, Apoptosis, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinase 1, MAP Kinase Signaling System, CD40 Ligand, Cell Line, Tumor, Mitogen-Activated Protein Kinase 3, Cell Proliferation, Mice, B-Cell Activating Factor

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