Journal
BLOOD
Volume 123, Issue 21, Pages 3277-3285Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-11-539049
Keywords
-
Categories
Funding
- Carol Shepherd Fund
- Royal Liverpool University Hospital Leukemia Fund
- Isle of Man Anti-Cancer Fund
- Leukemia and Lymphoma Research, United Kingdom
Ask authors/readers for more resources
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-kappa B pathways. PRDM1 induction was inversely correlated with the extent of anergy as measured by the ability to mobilize intracellular Ca2+ 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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available