Impact of bone marrow stromal cells on Bcl-2 family members in chronic lymphocytic leukemia

• Published in: Leukemia & lymphoma Vol. 55; no. 4; pp. 899 - 910
• Main Authors: Patel, Viralkumar, Chen, Lisa S., Wierda, William G., Balakrishnan, Kumudha, Gandhi, Varsha
• Format: Journal Article
• Language: English
• Published: United States Informa Healthcare 01.04.2014; Taylor & Francis
• Subjects: Apoptosis; Apoptosis - genetics; Bcl-2 family members; Cell Survival; chronic lymphocytic leukemia; Coculture Techniques; Gene Expression Profiling; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Mesenchymal Stem Cells - metabolism; microarray; microenvironment; mRNA; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; RNA, Messenger - genetics; Transcription, Genetic
• ISSN: 1042-8194; 1029-2403
• DOI: 10.3109/10428194.2013.819573

Abstract Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the Western world. High levels of Bcl-2 family anti-apoptotic proteins are responsible for apoptosis resistance. Besides anti-apoptotic proteins, the microenvironment provides substantial survival signals to CLL leukemic cells. However, in-depth knowledge on the role of individual Bcl-2 family members in the context of the microenvironment is still limited. We performed a comprehensive analysis of transcripts and proteins of 18 Bcl-2 family members using an "apoptosis array microfluidic card" in primary cells before and after stromal co-cultures. Our data showed that five of six anti-apoptotic members (excluding Bcl-b), two of three pro-apoptotic members (excluding Bok) and six of nine BH3-only members were present at detectable mRNA levels in CLL cells. Importantly, stromal-mediated extended survival of CLL cells was strongly associated with elevated global transcription. Upon co-culturing with stromal cells, there was an early response of an increase in anti- (2/5) and pro-apoptotic protein (3/8) transcripts on day 1, while an increase in anti-apoptotic proteins was observed on day 3, with no significant change in pro-apoptotic proteins. Our study revealed a differential pattern of expression of both transcripts and proteins following stromal co-cultures, proposing a significance of Bcl-2 family members in the stromal microenvironment.