Transcriptional and post-transcriptional mechanisms of BAFF-receptor dysregulation in human B lineage malignancies

Stephen A. Mihalcik, Renee C. Tschumper, Diane F. Jelinek

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Together, circulating BAFF and dominant receptor BAFF-R homeostatically regulate the humoral immune system. Consistently aberrant BAFF-R expression in leukemic cells reveals an intimate connection of these cells' malignant physiology to the BAFF/BAFF-R axis and also provides an additional survival mechanism to the expressing cells. In this study, we used primary cells and cell lines to interrogate the mechanisms underlying aberrant BAFF-R expression in precursor B acute lymphoblastic leukemia (precursor B-ALL) and mature B chronic lymphocytic leukemia (CLL). Here we demonstrate the aberrant expression of BAFF-R in precursor B-ALL cell lines and reveal that these cells acquire BAFF-R expression through premature transcriptional activation of the BAFF-R promoter in coordination with regulatory transcription factor c-Rel. Investigations using primary CLL cells provide a crucial counterpoint through their paucity of BAFF-R relative to their benign mature B cell counterparts, which we establish as functionally significant in its depletion of the CLL cells' BAFF-binding capacity. Furthermore, BAFF-R downregulation in CLL patients is revealed here to be restricted to the malignant compartment and mediated post-transcriptionally in order to compensate for the consistently unchanged levels of transcription factor c-Rel and BAFF-R mRNA. Finally, we present evidence that CLL cells retain endogenous mechanisms of BAFF-R regulatory control despite active receptor dysregulation.

Original languageEnglish (US)
Pages (from-to)4884-4892
Number of pages9
JournalCell Cycle
Volume9
Issue number24
DOIs
StatePublished - Dec 15 2010

Keywords

  • Acute lymphoblastic leukemia
  • BAFF
  • Baff receptor
  • Chronic lymphocytic leukemia
  • c-Rel

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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