Aldehyde dehydrogenase-1a1 induces oncogene suppressor genes in B cell populations

Abstract

The deregulation of B cell differentiation has been shown to contribute to autoimmune disorders, hematological cancers, and aging. We provide evidence that the retinoic acid-producing enzyme aldehyde dehydrogenase 1a1 (Aldh1a1) is an oncogene suppressor in specific splenic IgG1+/CD19− and IgG1+/CD19+ B cells populations. Aldh1a1 regulated transcription factors during B cell differentiation in a sequential manner: 1) retinoic acid receptor alpha (Rara) in IgG1+/CD19− and 2) zinc finger protein Zfp423 and peroxisome proliferator-activated receptor gamma (Pparg) in IgG1+/CD19+ splenocytes. In Aldh1a1−/− mice, splenic IgG1+/CD19− and IgG1+/CD19+ B cells acquired expression of proto-oncogenic genes c-Fos, c-Jun, and Hoxa10 that resulted in splenomegaly. Human multiple myeloma B cell lines also lack Aldh1a1 expression; however, ectopic Aldh1a1 expression rescued Rara and Znf423 expression in these cells. Our data highlight a mechanism by which an enzyme involved in vitamin A metabolism can improve B cell resistance to oncogenesis.

Network analysis of psoriasis reveals biological pathways and roles for coding and long non-coding RNAs

“…HOXA10 , is a homeobox gene that encodes a DNA-binding transcription factor that has been implicated in endometriosis [33], oncogenesis [34], and most recently in innate immune response regulation [35]. In a study of B cell differentiation, Yasmeen et al [36] demonstrated that the knockout of an aldehyde dehydrogenase-1 enzyme involved in retinol metabolism and retinoic acid synthesis and encoded by the ALDH1 family of genes resulted in increased expression of HOXA10 by downregulating the expression of the anti-inflammatory transcription factor peroxisome proliferator-activated receptor PPARG. ALDH1L1 , another hub gene in the blue module, is negatively coexpressed with HOXA10 and while PPARG is not a hub gene in the blue module, it is significantly downregulated in PPvNN.…”

Inflammation rapidly modulates the expression of ALDH1A1 (RALDH1) and vimentin in the liver and hepatic macrophages of rats in vivo

“…Thus, a further understanding its regulation in vivo is crucial. ALDH1A1 has been studied most extensively in the eye [ 10 ], but it is known to be expressed more broadly [ 1 – 3 ], including in the fetal and adult liver [ 3 , 5 , 11 ], lung, kidney, spleen, stomach, intestine, brain, heart, muscle and thymus [ 3 , 12 – 15 ], and certain cells of the immune system [ 3 – 5 , 12 – 14 , 16 , 17 ].…”

ZNF423: Transcriptional modulation in development and cancer

“…More recently, Yasmeen and co-workers reported that aldehyde dehydrogenase enzymes exert a positive regulatory influence on Zfp423 expression via RA signaling. 15 Additionally, ZNF423 is able to bind conserved enhancers in introns 3 and 5 of its own gene in both human and mouse cellular models, thereby repressing its own transactivation and suggesting a negative autoregulatory feedback loop under high ZNF423 expression levels (Fig. 1B).…”