A major new study has identified key changes that make follicular lymphoma aggressive, and has pointed to potential treatments with new experimental drugs.
Researchers in New York and Texas, USA, and British Columbia, Canada, have undertaken laboratory studies that suggest BAF inhibitors in development might successfully treat the follicular lymphomas which carry the mutations.
The researchers say that until now the reasons for the disease becoming aggressive have not been known – making it very hard to predict if patients are at risk.
Reporting in Cancer Cell, the researchers studied mutations in the ARID1A gene, found in a significant number of follicular lymphoma patients. The mutations disrupt the activity of the BAF complex, a multi-protein molecular “machine” which is a major regulator of gene activity. BAF mutations occur in many cancers.
The study showed that ARID1A mutations in B cells steers them towards becoming unusually immature memory B cells. This led to rapid cell division and mutation and inconsistent expression of antibodies needing to tackle infections.
Dr Darko Barisic, joint first author of the study, said: “These findings suggest that ARID1A is effectively a tumour suppressor, whose deficiency in follicular lymphoma promotes the transformation to a more aggressive lymphoma.”
However, in further studies in mice, the team showed ARID1A mutations make the cancer sensitive to drugs which block the functions of the BAF complex – with some mice going into complete remission with these experimental drugs alone.
Study leader Professor Ari Melnick, of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, said: “These data raise the possibility of developing early intervention precision therapies for those follicular lymphoma patients at risk for rapid progression, who currently do not have such options.”
Source:
Barisic D, Chin CR, Meydan C, Teater M, Tsialta I, Mlynarczyk C, Chadburn A, Wang X, Sarkozy M, Xia M, Carson SE, Raggiri S, Debek S, Pelzer B, Durmaz C, Deng Q, Lakra P, Rivas M, Steidl C, Scott DW, Weng AP, Mason CE, Green MR, Melnick A. (2024) “ARID1A orchestrates SWI/SNF-mediated sequential binding of transcription factors with ARID1A loss driving pre-memory B cell fate and lymphomagenesis.” Cancer Cell, 7 March 2024, doi: 10.1016/j.ccell.2024.02.010
Link: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00054-0
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