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Lela Kardava, Qi Yang, Anthony St. Leger, Kenneth A. Foon, Suzanne Lentzsch, Abbe N. Vallejo, Christine Milcarek, Lisa Borghesi, The B lineage transcription factor E2A regulates apoptosis in chronic lymphocytic leukemia (CLL) cells, International Immunology, Volume 23, Issue 6, June 2011, Pages 375–384, https://doi.org/10.1093/intimm/dxr027
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Abstract
Chronic lymphocytic leukemia (CLL) is a common malignancy characterized by the accumulation of B lymphocytes with an antigen-experienced activated CD19+CD5+ clonal phenotype. Clinically, ∼50% of cases will behave more aggressively. Here, we investigate the role of the major B-cell transcription factor E2A, a known regulator of B-cell survival and proliferation, to CLL persistence. We show that E2A is elevated at the mRNA and protein levels relative to normal B-cell subsets. E2A silencing in primary CLL cells leads to a significant increase in spontaneous apoptosis in both CD38+ (aggressive) and CD38− (indolent) cases. Moreover, E2A knockdown synergizes with the immunomodulatory drug lenalidomide to reduce CLL viability. E2A is known to restrain the proliferation of primary B and T lymphocytes at multiple stages of maturation and we report that targeted E2A disruption increases the frequency of Ki-67+ CLL cells in the absence of effects on de novo proliferation. At the molecular level, E2A siRNA-treated CLL cells display reduced expression of key genes associated with survival and cell cycling including p27, p21 and mcl-1, of which the former two are known E2A target genes. Thus, E2A, a key transcription factor associated with the B-cell activation profile, regulates apoptosis in CLL and may contribute to disease pathology.
