title: Variable induction of PRDM1 and differentiation in chronic lymphocytic leukemia is associated with anergy.
abstract: Despite antigen engagement and intact B-cell-receptor (BCR) signaling, chronic lymphocytic leukemia (CLL) cells fail to undergo terminal differentiation. We hypothesized that such failure may be due to anergy, as CLL cells exhibit variable levels of nonresponsiveness to surface IgM stimulation that is reversible in vitro. Moreover, anergy is associated with reduced differentiation capacity in normal B cells. We investigated responses of CLL cells to two potent differentiation-promoting agents, IL-21 and cytosine guanine dinucleotide-enriched oligo-deoxynucleotides. The induction of PR domain-containing protein 1 (PRDM1; also known as Blimp-1), a critical regulator of plasmacytic differentiation, by these agents was closely correlated but varied between individual cases, despite functionally intact IL-21 receptor- and Toll-like receptor 9-mediated signal transducer and activator of transcription 3, and nuclear factor-κB pathways. PRDM1 induction was inversely correlated with the extent of anergy as measured by the ability to mobilize intracellular Ca(2+) following BCR crosslinking. PRDM1 responsiveness was associated with other markers of differentiation and proliferation but not with differences in apoptosis. The ability to induce PRDM1 did correlate with differential transcriptional and epigenetic regulation of the PRDM1 gene. These studies extend our understanding of CLL pathobiology, demonstrating that reduced differentiation capacity may be a consequence of anergy. Epigenetic drugs may offer possibilities to reactivate PRDM1 expression as part of novel differentiation therapy approaches.
authors.affiliation: Haematology, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and.
authors.forename: Andrew
authors.identifier: http://orcid.org/0000-0003-3067-2951
authors.initials: A
authors.lastname: Duckworth
authors.affiliation: Haematology, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and.
authors.forename: Mark
authors.initials: M
authors.lastname: Glenn
authors.affiliation: Haematology, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Slupsky
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
authors.affiliation: Haematology, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and.
authors.forename: Nagesh
authors.initials: N
authors.lastname: Kalakonda
mesh_terms: D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D017635:Clonal Anergy; D015226:Dinucleoside Phosphates / Q000276:immunology*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D007378:Interleukins / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000235:genetics* / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D015226:Dinucleoside Phosphates; D007075:Immunoglobulin M; D007378:Interleukins; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins; D000098546:Interleukin-21; C087042:PRDM1 protein, human; C015772:CpG dinucleotide