BCL-W has a fundamental role in B cell survival and lymphomagenesis

Adams, Clare M.; Kim, Annette S.; Mitra, Ramkrishna; Choi, John K.; Gong, Jerald Z.; Eischen, Christine M.

doi:10.1172/jci89486

Cited by 46 publications

(65 citation statements)

References 57 publications

(81 reference statements)

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“…Recently, after analyzing microarray data sets containing 57 Burkitt and 319 DLBCL patient samples, we reported that BCLW is frequently overexpressed in both of these lymphomas (9). Since RNA-sequencing data sets were limited, we obtained additional microarray data sets of DLBCL and normal human B-cells and combined them with those we previously analyzed.…”

Section: Resultsmentioning

confidence: 99%

“…Using two independent data sets containing survival data, we previously reported DLBCL patients with high levels of BCLW and low levels of BCL2 had poor survival compared to patients whose DLBCL was low for both BCLW and BCL2 (9). To assess whether this was specific for ABC or GCB DLBCL, we evaluated overall survival of each subtype based on BCLW and BCL2 expression.…”

Section: Resultsmentioning

confidence: 99%

“…We recently discovered that Burkitt lymphomas frequently overexpress BCLW, an anti-apoptotic BCL2 family member that was initially reported to only function in spermatogenesis (7,8). Targeting BCLW with shRNA or pharmacologically with BH3-mimetics induced apoptosis in Burkitt lymphoma cell lines, indicating BCLW was required for its survival (9). When overexpressed, BCLW conferred resistance to BH3-mimetics (9).…”

Section: Introductionmentioning

confidence: 99%

“…Targeting BCLW with shRNA or pharmacologically with BH3-mimetics induced apoptosis in Burkitt lymphoma cell lines, indicating BCLW was required for its survival (9). When overexpressed, BCLW conferred resistance to BH3-mimetics (9). We also showed that DLBCL frequently overexpresses BCLW alone or in combination with BCL2, and that increased levels of BCLW in patient samples with low BCL2 expression correlated with reduced patient survival (9).…”

Section: Introductionmentioning

confidence: 99%

“…When overexpressed, BCLW conferred resistance to BH3-mimetics (9). We also showed that DLBCL frequently overexpresses BCLW alone or in combination with BCL2, and that increased levels of BCLW in patient samples with low BCL2 expression correlated with reduced patient survival (9). Therefore, BCLW is a previously unappreciated, significant contributor to Burkitt lymphoma and DLBCL, but its involvement in other B-cell lymphomas is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Non-Hodgkin and Hodgkin Lymphomas Select for Overexpression of BCLW

Adams

Mitra

Gong

et al. 2017

Clinical Cancer Research

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Purpose B-cell lymphomas must acquire resistance to apoptosis during their development. We recently discovered BCLW, an anti-apoptotic BCL2 family member thought only to contribute to spermatogenesis, was overexpressed in diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. To gain insight into the contribution of BCLW to B-cell lymphomas and its potential to confer resistance to BCL2 inhibitors, we investigated the expression of BCLW and the other anti-apoptotic BCL2 family members in six different B-cell lymphomas. Experimental Design We performed a large-scale gene expression analysis of data sets comprising approximately 2300 lymphoma patient samples, including non-Hodgkin and Hodgkin lymphomas as well as indolent and aggressive lymphomas. Data were validated experimentally with qRT-PCR and immunohistochemistry. Results We report BCLW is significantly overexpressed in aggressive and indolent lymphomas, including DLBCL, Burkitt, follicular, mantle cell, marginal zone, and Hodgkin lymphomas. Notably, BCLW was preferentially overexpressed over that of BCL2 and negatively correlated with BCL2 in specific lymphomas. Unexpectedly, BCLW was overexpressed as frequently as BCL2 in follicular lymphoma. Evaluation of all five anti-apoptotic BCL2 family members in six types of B-cell lymphoma revealed that BCL2, BCLW, and BCLX were consistently overexpressed, whereas MCL1 and A1 were not. Additionally, individual lymphomas frequently overexpressed more than one anti-apoptotic BCL2 family member. Conclusions Our comprehensive analysis indicates B-cell lymphomas commonly select for BCLW overexpression in combination with or instead of other anti-apoptotic BCL2 family members. Our results suggest BCLW is likely equally as important in lymphomagenesis as BCL2 and that targeting BCLW in lymphomas should be considered.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Non-Hodgkin and Hodgkin Lymphomas Select for Overexpression of BCLW

Adams

Mitra

Gong

et al. 2017

Clinical Cancer Research

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Principles for Understanding Mechanisms of Cell Death and Their Role in Cancer Biology

Diepstraten

Marca

and

2023

Precision Cancer Therapies, Volume 1 ‐ Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies

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BCL-2 protein family: attractive targets for cancer therapy

2022

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Acquired resistance to cell death is a hallmark of cancer. The BCL-2 protein family members play important roles in controlling apoptotic cell death. Abnormal over-expression of pro-survival BCL-2 family members or abnormal reduction of pro-apoptotic BCL-2 family proteins, both resulting in the inhibition of apoptosis, are frequently detected in diverse malignancies. The critical role of the pro-survival and pro-apoptotic BCL-2 family proteins in the regulation of apoptosis makes them attractive targets for the development of agents for the treatment of cancer. This review describes the roles of the various pro-survival and pro-apoptotic members of the BCL-2 protein family in normal development and organismal function and how defects in the control of apoptosis promote the development and therapy resistance of cancer. Finally, we discuss the development of inhibitors of pro-survival BCL-2 proteins, termed BH3-mimetic drugs, as novel agents for cancer therapy.

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BCL-W has a fundamental role in B cell survival and lymphomagenesis

Cited by 46 publications

References 57 publications

Non-Hodgkin and Hodgkin Lymphomas Select for Overexpression of BCLW

Non-Hodgkin and Hodgkin Lymphomas Select for Overexpression of BCLW

Principles for Understanding Mechanisms of Cell Death and Their Role in Cancer Biology

BCL-2 protein family: attractive targets for cancer therapy

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