Investigators at the Sidney Kimmel Cancer Center at Jefferson uncovered potential new culprits that contribute to the development and progression of several types of lymphoma. The study was published in a recent issue of Clinical Cancer Research, with co-first authors Drs. Clare M. Adams and Ramkrishna Mitra, along with co-author Dr. Jerald Z. Gong and senior author Christine Eischen, PhD, Vice Chair of the Department of Cancer Biology at Thomas Jefferson University.
The researchers focused their attention on a related group of proteins termed the BCL2 family, members of which can positively and negatively regulate cell death. Achieving a proper balance of cell death and cell survival is a key aspect of normal tissue differentiation and maintenance, and abnormal situations that enhance cell survival, such as over-expression of a pro-survival factor or loss of a cell death-promoting factor, can confer a growth advantage to cells and thereby promote cancer development and progression. The investigators therefore undertook a systematic analysis of all five anti-apoptotic BCL2 family members in about 2,300 lymphoma patient samples representing six B-cell lymphomas, including Burkitt, diffuse large B-cell, follicular, marginal zone, mantle cell, and Hodgkin lymphoma.
This approach revealed that all six B-cell lymphomas are frequently associated with over-expression of the BCL2 family member BCLW (see figure), and other BCL2 family members are often over-expressed as well in some lymphoma subtypes. As Eischen explained, “These data suggest BCLW is a critical survival factor in multiple B-cell lymphomas and likely is as important in lymphoma as BCL2, the founding member of this protein family. Our results also suggest that targeting BCLW in lymphomas should be considered.”
The study has important implications for developing new clinical approaches to treat B-cell lymphomas. At present, there is a major ongoing pharmaceutical effort to therapeutically target specific BCL2 members in lymphoma, but BCLW has been ignored. By analyzing expression of all anti-apoptotic BCL2 family members in a large dataset of roughly 2,300 lymphoma patient samples, the investigators were able to determine that BCLW was selected for over-expression, and they identified other anti-apoptotic BCL2 members that were over-expressed in certain lymphoma subtypes, and which therefore should cooperate with BCLW to protect those lymphoma cells from dying in those patients.
“Our results indicate that targeting BCLW in B-cell lymphomas alone or in combination with other specific BCL2 family inhibitors should be considered and is likely needed, and our analysis will help identify those patients most likely to respond to specific BCL2 family inhibitors,” Eischen said. “Furthermore, our data suggest that targeting just one anti-apoptotic BCL2 family member may lead to dependence on another, resulting in therapy resistance.”
In terms of future directions, the investigators envision development of BCLW-specific inhibitors that will be tested for therapeutic efficacy on B-cell lymphomas and potentially other malignancies.