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<p>Loss of BLM helicase leads to Bloom Syndrome, characterized by genomic instability, cancer predisposition and immunodeficiency. We now show that BLM is essential for the proliferation of cycling B cells and sustains B-cell development by maintaining NF-κB signalling. Hence, in the absence of BLM, the NF-κB pathway is impaired as visualized by the lack of the nuclear translocation of RelA. This action of BLM is due to its binding to the MALT1 promoter (a key positive regulator of NF-κB signalling) and activating its transcription. Reintroduction of MALT1 and constitutively active IKKβ rescues B-cell development in BLM-deficient bone marrow and spleen cells of BLM knockout mice. This indicates that downregulation of MALT1 in BLM-deficient cells is the primary cause of deregulated NF-κB signalling and impaired B-cell development. Interestingly, the pro-proliferative role of BLM can be exploited in the treatment of B-cell malignancies. Here, we demonstrate that depletion of BLM (phenocopied by the inhibition of MALT1) suppresses the progression of lymphoma and leukaemia by inhibiting MALT1-dependent NF-κB signalling and sensitizing malignant B cells to chemotherapy. Together, our findings establish the BLM-MALT1-NF-κB axis as a critical regulator of B-cell development and demonstrate its therapeutic potential in B-cell malignancies. Hence, both upregulation and downregulation of BLM contribute to oncogenesis, underscoring the need to maintain its expression within a tightly controlled threshold.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Ritu Agrawal,
  • Supratim Ghosh,
  • Nitin Kumar,
  • Chetana Mukherjee,
  • Vandana Sharma,
  • Rimpy Arun,
  • Riya Deb,
  • Sumanta Sarkar,
  • Savita,
  • Dilip Kumar,
  • Satyajit Rath,
  • Arindam Maitra,
  • Sagar Sengupta

摘要

Loss of BLM helicase leads to Bloom Syndrome, characterized by genomic instability, cancer predisposition and immunodeficiency. We now show that BLM is essential for the proliferation of cycling B cells and sustains B-cell development by maintaining NF-κB signalling. Hence, in the absence of BLM, the NF-κB pathway is impaired as visualized by the lack of the nuclear translocation of RelA. This action of BLM is due to its binding to the MALT1 promoter (a key positive regulator of NF-κB signalling) and activating its transcription. Reintroduction of MALT1 and constitutively active IKKβ rescues B-cell development in BLM-deficient bone marrow and spleen cells of BLM knockout mice. This indicates that downregulation of MALT1 in BLM-deficient cells is the primary cause of deregulated NF-κB signalling and impaired B-cell development. Interestingly, the pro-proliferative role of BLM can be exploited in the treatment of B-cell malignancies. Here, we demonstrate that depletion of BLM (phenocopied by the inhibition of MALT1) suppresses the progression of lymphoma and leukaemia by inhibiting MALT1-dependent NF-κB signalling and sensitizing malignant B cells to chemotherapy. Together, our findings establish the BLM-MALT1-NF-κB axis as a critical regulator of B-cell development and demonstrate its therapeutic potential in B-cell malignancies. Hence, both upregulation and downregulation of BLM contribute to oncogenesis, underscoring the need to maintain its expression within a tightly controlled threshold.