Human CD38, located on the short arm of chromosome 4 (4p15), exhibits a number of unique features. First, the gene is relatively large, with > 98% of the genetic material consisting of introns. The promoter region is atypical, lacking a canonical TATA box, but containing a CpG island, pointing to epigenetic regulatory mechanisms, yet to be demonstrated.
CD38 expression by peripheral blood mononuclear cells behaves as a polymorphic trait in the general population, in keeping with the notion that the gene is under the pressure of constant and intense regulatory activity. Retinoids, vitamin D, and a variety of cytokines are the most known inducers.
(Now you see my reticence in endorsing megadoses of vitamin D for the general CLL population. It could theoretically increase CD38 expression.)
Besides being variable among CLL patients, CD38 expression can change at anatomic sites, being higher in BM and in areas of intense CLL/T lymphocyte contact. Accordingly, during CLL cell activation in vitro, CD38 expression can be up-regulated by a number of different signals, such as IL-2, CD40L plus IL-4, CpG oligonucleotides, and coculture with mesenchymal stem cells.
A single nucleotide polymorphism (C > G, rs6449182) is located at the 5′ end of intron 1 of CD38, and allelic frequencies of the polymorphism in healthy Italian, Spanish, Irish, and Polish populations have been defined. The frequency of the G allele is significantly higher in a subset of CLL patients exhibiting clinical and molecular markers of poor prognosis. The highest frequency is found in patients with Richter syndrome (RS), with the G allele representing an independent risk factor for RS. The same G allele is a susceptibility factor for CLL development in the Polish population. Furthermore, there are no significant differences in the percentage of CD38+ cells or intensity of expression in circulating CLL lymphocytes of G carriers and CC homozygotes in these populations, whereas environmental signals lead to greater increases in CD38 expression selectively in G carriers. The latter suggests involvement of the single nucleotide polymorphism (SNP) in transcription, possibly because the C > G SNP is located within a binding site for E47, the predominantly active isoform of E2A in human B lymphocytes that binds canonical E-box elements and activates gene transcription. These events are essential in the programs regulating B-cell differentiation by controlling Ig gene transcription and recombination as well as expression of other B-lineage genes. E47 is effectively recruited to the regulatory region of CD38 and the CD38 genotype in the E-box conditions the strength of the binding. E2A shows a comparatively higher affinity for the G allele, linking CD38 genotype to the dynamic regulation of surface expression of the molecule. The finding that E2A directly drives transcription of AICDA, in turn responsible for class switch recombination and somatic hypermutation, opens the possibility that the interplay between E47 and CD38 may lead to increased susceptibility to the insurgence of RS.
In line with the presence of a CpG island, the CD38 promoter can be methylated and methylation negatively correlates with surface expression. In a study of 168 CLL patients and using a cut-off of 7% for surface CD38 expression, 96% of CD38− persons exhibited methylation, whereas only 25% of CD38+ samples were methylated.
Methylation was not observed in peripheral blood mononuclear cells of healthy controls. Given that the defect appears to be site-specific and not a global event in CLL patients, it is foreseeable that it will become a useful predictor of outcome.