Chronic Lymphocytic Leukemia: Disease Biology

Authors

Stefan Koehrer
Jan A Burger

Language

English

Publication Date

1-1-2024

Journal

Acta Haematologica

DOI

10.1159/000533610

PMID

37717577

PMCID

PMC11753505

PubMedCentral® Posted Date

1-22-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Background: B-cell receptor (BCR) signaling is crucial for normal B-cell development and adaptive immunity. In chronic lymphocytic leukemia (CLL), the malignant B cells display many features of normal mature B lymphocytes, including the expression of functional B-cell receptors (BCRs). Cross talk between CLL cells and the microenvironment in secondary lymphatic organs results in BCR signaling and BCR-driven proliferation of the CLL cells. This critical pathomechanism can be targeted by blocking BCR-related kinases (BTK, PI3K, spleen tyrosine kinase) using small-molecule inhibitors. Among these targets, Bruton tyrosine kinase (BTK) inhibitors have the highest therapeutic efficacy; they effectively block leukemia cell proliferation and generally induce durable remissions in CLL patients, even in patients with high-risk disease. By disrupting tissue homing receptor (i.e., chemokine receptor and adhesion molecule) signaling, these kinase inhibitors also mobilize CLL cells from the lymphatic tissues into the peripheral blood (PB), causing a transient redistribution lymphocytosis, thereby depriving CLL cells from nurturing factors within the tissue niches.

Summary: The clinical success of the BTK inhibitors in CLL underscores the central importance of the BCR in CLL pathogenesis. Here, we review CLL pathogenesis with a focus on the role of the BCR and other microenvironment cues.

Key messages: (i) CLL cells rely on signals from their microenvironment for proliferation and survival. (ii) These signals are mediated by the BCR as well as chemokine and integrin receptors and their respective ligands. (iii) Targeting the CLL/microenvironment interaction with small-molecule inhibitors provides a highly effective treatment strategy, even in high-risk patients.

Keywords

Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Signal Transduction, Receptors, Antigen, B-Cell, Cell Proliferation, Biology, Protein Kinase Inhibitors, Tumor Microenvironment, Chronic lymphocytic leukemia, Microenvironment, B-cell receptor, Nurse-like cells, Chemokine receptors, BTK, PI3K, Spleen tyrosine kinase, Ibrutinib

Published Open-Access

yes

Recommended Citation

Stefan Koehrer and Jan A Burger, "Chronic Lymphocytic Leukemia: Disease Biology" (2024). Faculty, Staff and Student Publications. 5396.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5396