The role of vitamin A metabolites in human and murine B cells

Abstract

Unraveling mechanisms regulating gammopathies, abnormal immunoglobulin production is necessary to improve treatments of a number of blood cancers, such as multiple myeloma. Retinoic acid and retinaldehyde, a transcriptionally active metabolites of vitamin A, play a key role in differentiation processes. RA is produced by the aldehyde dehydrogenase‐1 family of enzymes (Aldh1a1, a2, a3). Our objective was to identify key genes regulating the cellular levels of these metabolites.Our studies in healthy subjects’ showed that Aldh1a1 is the predominantly expressed Aldh1 enzyme in circulating B cells comprising majority of PBMC fraction. In contrast, two myeloma B cell lines, U266 and RPMI8226 lack Aldh1a1 expression. PBMC from multiple myeloma patients showed an expression profile similar to that of U266. We showed that similar to human B cells, naïve (CD19−) and committed (CD19+) splenic B cells from WT mice predominantly expressed Aldh1a1, whereas in Aldh1a1−/− mice these B cells were complete depleted of Aldh1 expression. In both genotypes B cell differentiation from CD19− to CD19+ phenotype was associated with the loss of Aldh1a1 and a2. The change in the RA production in CD19− and CD19+ cells was accompanied by changed levels of key proteins such as RARa, HoxA10, and PPARg. Our studies suggest that Aldh1 enzymes are important for regulation of Ig production and their deficiency is associated with malignant B cells.Grant Funding Source: Nutrition (ASN)