Suspect eliminated as a therapeutic target in B cell lymphoma

Suspect eliminated as a therapeutic target in B cell lymphoma

5 February 2020
Walter and Eliza Hall Institute researchers have narrowed the focus on which survival proteins are important for the survival of B cell lymphomas, eliminating the protein BCL-W from the ‘suspect list’.

Smiling researchers
Dr Sarah Diepstraten and Dr Gemma Kelly have eliminated
the protein BCL-W from the 'suspect list' of proteins that
help B cell lymphoma cells to survive.

Using gene editing technology, the research team showed that human B cell lymphoma cell lines can survive without BCL-W – dismissing this protein as a potential therapeutic target for these particular B cell lymphomas. The discovery upends earlier speculation that BCL-W could be an important survival factor for B cell lymphomas, and will focus future research efforts on more important targets.

The research, led by Dr Gemma Kelly and Dr Sarah Diepstraten, was published in the journal Blood Advances.

At a glance

  • BCL-W is a protein that prevents apoptotic cell death. Earlier research had suggested that BCL-W may be important for the survival of B cell lymphomas, making it an attractive therapeutic target.
  • Our researchers showed that BCL-W was not required for the survival of human B cell lymphoma cell lines.
  • This discovery suggests that medicines targeting BCL-W would not be effective treatments for the majority of B cell lymphomas.

Lymphoma survival factors

BCL-W is a member of the BCL-2 protein family, and promotes cancer cell survival by inhibiting apoptotic cell death. Other pro-survival members of the BCL-2 family, including the proteins BCL-2 and MCL-1, have shown promise as targets for anti-cancer drugs, particularly for certain leukaemias and lymphomas.

Dr Kelly said that recent research from other groups showed that many B cell lymphomas had increased levels of BCL-W, suggesting that this protein may promote cancer cell survival.

“This led to speculation that drugs targeting BCL-W could be useful for treating B cell lymphomas,” she said.

Eliminating a suspect

To investigate whether inhibiting BCL-W could be effective in treating B cell lymphomas, the team reduced the amount of BCL-W protein within B cell lymphoma cell lines.

Dr Diepstraten said that in the B cell lymphoma cell lines tested, losing BCL-W did not impact cell survival. “We showed BCL-W was not required by these lymphoma cells, suggesting that drugs targeting BCL-W would not be effective treatments for all B cell lymphomas,” Dr Diepstraten said.

“We also investigated the possibility that high levels of BCL-W in lymphomas might cooperate with other related survival proteins, such as BCL-2 or MCL-1, to promote survival,” she said. “However, this was not the case: loss of BCL-W did not sensitise lymphoma cells to drugs that inhibit BCL-2 or MCL-1.”

Shifting focus

Dr Kelly said the results showed that, at least for certain B cell lymphomas, targeting BCL-W should not be a priority for future research and drug development. “It is likely that other pro-survival proteins are much more important in these diseases,” she said.

“BCL-W is considered to be a particularly appealing therapeutic target because it is not required for the function of most normal (non-cancerous) cells in the body, so we would not expect drugs targeting BCL-W to have significant side-effects.

“While BCL-W may not be a critical survival factor for B cell lymphomas, it is possible that BCL-W may contribute to the survival or drug resistance of other types of cancer – meaning that BCL-W inhibitors could be relevant in these cases,” Dr Kelly said.

The work extends the Walter and Eliza Hall Institute’s long-term interest in the proteins controlling apoptosis, and how they contribute to diseases including cancer. BCL-W was in fact discovered at the Institute – the ‘W’ stands for Walter and Eliza Hall Institute.

The research was supported by the Australian National Health and Medical Research Council of Australia, the Victorian Cancer Agency, Cancer Council Victoria, the Leukaemia Foundation Australia, the US Leukemia and Lymphoma Society, the estate of Anthony (Toni) Redstone OAM, the Craig Perkins Cancer Research Foundation and the Victoria Government.

 

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