BLM regulates MALT1-driven NF-κB signalling and is targetable in B-cell malignancies

Area of Science:

• Molecular Biology
• Immunology
• Cancer Biology

Background:

• Bloom Syndrome is caused by BLM helicase loss, leading to genomic instability, cancer, and immunodeficiency.
• BLM helicase is vital for B cell proliferation and development, maintaining NF-κB signaling pathways.

Purpose of the Study:

• To investigate the role of BLM helicase in B cell development and NF-κB signaling.
• To explore the therapeutic potential of targeting the BLM-MALT1-NF-κB axis in B cell malignancies.

Main Methods:

• Utilized BLM knockout mice to study B cell development.
• Analyzed NF-κB pathway activation, including RelA nuclear translocation.
• Investigated BLM's interaction with the MALT1 promoter.
• Assessed the effects of MALT1 reintroduction and IKKβ activation.
• Examined BLM depletion and MALT1 inhibition in lymphoma and leukemia models.

Main Results:

• BLM deficiency impairs B cell development by disrupting NF-κB signaling due to reduced MALT1 transcription.
• Restoring MALT1 or IKKβ function rescues B cell development in BLM-deficient cells.
• BLM depletion, similar to MALT1 inhibition, suppresses lymphoma and leukemia progression.
• Malignant B cells are sensitized to chemotherapy upon BLM or MALT1 inhibition.

Conclusions:

• The BLM-MALT1-NF-κB axis is essential for normal B cell development.
• Targeting this axis offers therapeutic potential for B cell malignancies.
• Maintaining a controlled threshold of BLM expression is critical to prevent oncogenesis.