Non-Hodgkin Lymphoma (NHL) is a collective name for cancers that develop from white blood cells (lymphocytes) in the lymphatic system. Originating from B lymphocytes, diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are aggressive types of NHL. Several forms of treatments are available for patients with DLBL or MCL varying from chemotherapy, radiation therapy, immunotherapy, or combination therapies with precision drugs. In addition, bone marrow stem cell transplantation may be considered. However, to improve treatment effectiveness and patient prognosis, a better understanding of the molecular basis of DLBL and MCL is needed.
Regulators of B cells growth
In a study recently published in Blood Cancer Journal, scientists from Cancer Center Amsterdam further unravel the driving forces behind aggressive B-cell lymphoma. Based on cancer cell lines and patient material, the research team led by Dr. Marcel Spaargaren discovered that that low expression of a protein called cylindromatosis (CYLD) was linked to a worse prognosis for patients with DLBCL and MCL.
CYLD normally plays a role in preventing the activation of a key cellular regulator, a transcription factor called NF-κB. When activated, this transcription factor promotes cell growth and survival by switching on numerous other genes.
Following this line of inquiry, the team further discovered that B-cell receptor (BCR) signaling was not functioning correctly. BCR signaling is a crucial process that is normally triggered when a B-cell binds to an antigen, setting off a cascade of effects that leads to immune system activation.
Identifying potentially new therapeutic targets
First author of the paper Marthe Mindermans explains: “We found that chronic BCR signaling results in the subsequent cleavage and disposal of CYLD by a specific protease called MALT1. The loss of CYLD leads to the uncontrolled activation of NF-κB – it is perpetually ‘on’ – enabling cells to grow aggressively.”
The study provides novel insights into the underlying molecular mechanisms driving lymphoma cell proliferation. “It also points at promising new therapeutical targets, such as inhibitors of the MALT1 protease for DLBCL, MCL, and potentially other B-cell malignancies,” adds principal investigator Marcel Spaargaren.
Pursuing new leads
To mimic blocking MALT1, the researchers designed a version of CYLD that was resistant to cleavage by the protease, and found that overexpression of this mutant in cell lines reduced NF-κB activity and growth of lymphoma cells.
Dr. Spaargaren: ”Our data show that understanding the molecular aberrations in cancer cells identify promising new ideas for targeted treatments. In addition, it points to way to the recognition of patients who are most likely to benefit because of matching molecular tumor signatures. Obviously, we are eager to pursue this and translate these new insights into clinical applications.”
For more information contact Dr. Spaargaren.
Minderman, M., Lantermans, H.C., Grüneberg, L.J. et al. MALT1-dependent cleavage of CYLD promotes NF-κB signaling and growth of aggressive B-cell receptor-dependent lymphomas. Blood Cancer J. 13, 37 (2023). https://doi.org/10.1038/s41408-023-00809-7
Researchers at Amsterdam UMC involved:
Marthe Minderman
Hildo C. Lantermans
Leonie J. Grüneberg
Saskia A. G. M. Cillessen
Richard J. Bende
Carel J. M. van Noesel
Marie José Kersten
Steven T. Pals
Marcel Spaargaren
Funding
This work is supported by grants from Lymph&Co
This article was created for Cancer Center Amsterdam.
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