The B lineage transcription factor E2A regulates apoptosis in chronic lymphocytic leukemia (CLL) cells.

[Guest guest]

BlankThe B lineage transcription factor E2A regulates apoptosis in chronic

lymphocytic leukemia (CLL) cells.

L Kardava, Q Yang, A St Leger, KA Foon, S Lentzsch, AN Vallejo, C Milcarek, and

L Borghesi

Int. Immunol., May 6, 2011;

Department of Immunology, University of Pittsburgh School of Medicine, 200

Lothrop Street, Pittsburgh, PA 15261, USA.

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.

PMID: 21551245