title: The B lineage transcription factor E2A regulates apoptosis in chronic lymphocytic leukemia (CLL) cells.
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.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, PA 15261, USA.
authors.forename: Lela
authors.initials: L
authors.lastname: Kardava
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.forename: Anthony
authors.initials: A
authors.lastname: St Leger
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Foon
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lentzsch
authors.forename: Abbe N
authors.initials: AN
authors.lastname: Vallejo
authors.forename: Christine
authors.initials: C
authors.lastname: Milcarek
authors.forename: Lisa
authors.initials: L
authors.lastname: Borghesi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D012333:RNA, Messenger; C407909:TCF3 protein, human