The chronic lymphocytic leukemia clone disrupts the bone marrow microenvironment

Area of Science:

• Hematology
• Oncology
• Cell Biology

Background:

• Chronic lymphocytic leukemia (CLL) B-cells localize to the bone marrow (BM).
• Mesenchymal stromal cells (MSCs) protect CLL cells from apoptosis in vitro.
• The in vivo impact of CLL cells on MSCs is debated.

Purpose of the Study:

• To investigate the impact of CLL cells on bone marrow mesenchymal stromal cells (MSCs).
• To analyze the functional and molecular characteristics of MSCs in the CLL BM microenvironment.

Main Methods:

• Quantification and expansion of colony-forming unit-fibroblasts (CFU-Fs) from CLL BM.
• Gene expression analysis of 384 selected genes.
• Analysis of secreted molecules and senescence markers (SA-βGAL, p16INK4a).
• Assessment of hematon structures in BM.

Main Results:

• CLL BM cultures showed significantly reduced CFU-F formation compared to normal BM, even with bFGF.
• CFU-Fs from CLL BM exhibited features of senescence, including altered morphology, low proliferation, and senescence-associated secretory phenotype.
• Hematon structures were rare or absent in CLL BM, with observed nodular B-CLL cell invasion.
• Hypoxic conditions did not rescue CFU-F function.

Conclusions:

• CLL B-cells induce senescence in bone marrow MSCs.
• The CLL clone significantly impacts MSCs, disrupting normal bone marrow organization in vivo.
• These findings raise new questions regarding the pathophysiology of CLL in the BM microenvironment.