Abstract
The Atypical ChemoKine Receptor 1 (ACKR1) gene, better known as Duffy Antigen Receptor for Chemokines (DARC or Duffy), is responsible for the Duffy Blood Group and plays a major role in regulating the circulating homeostatic levels of pro-inflammatory chemokines. Previous studies have shown that one common variant, the Duffy Null (Fy-) allele that is specific to African Ancestry groups, completely removes expression of the gene on erythrocytes; however, these individuals retain endothelial expression. Additional alleles are associated with a myriad of clinical outcomes related to immune responses and inflammation. In addition to allele variants, there are two distinct transcript isoforms of DARC which are expressed from separate promoters, and very little is known about the distinct transcriptional regulation or the distinct functionality of these protein isoforms. Our objective was to determine if the African specific Fy- allele alters the expression pattern of DARC isoforms and therefore could potentially result in a unique signature of the gene products, commonly referred to as antigens. Our work is the first to establish that there is expression of DARC on lymphoblasts. Our data indicates that people of African ancestry have distinct relative levels of DARC isoforms expressed in these cells. We conclude that the expression of both isoforms in combination with alternate alleles yields multiple Duffy antigens in ancestry groups, depending upon the haplotypes across the gene. Importantly, we hypothesize that DARC isoform expression patterns will translate into ancestry-specific inflammatory responses that are correlated with the axis of pro-inflammatory chemokine levels and distinct isoform-specific interactions with these chemokines. Ultimately, this work will increase knowledge of biological mechanisms underlying disparate clinical outcomes of inflammatory-related diseases among ethnic and geographic ancestry groups.
Highlights
The Duffy Antigen Receptor for Chemokines (DARC), recently renamed Atypical Chemokine Receptor 1 (ACKR1), expresses the red blood cell antigens that define the Duffy Blood Groups for which it was originally discovered [1, 2]
IHC analysis indicates varying levels of DARC/ACKR1 gene product among our cohort ancestry groups with the consistently the higher levels of in the African group lymphoblasts. This is in contrast to the Duffy Null phenotype status of these individuals, where of no DARC/ACKR1 is expressed on erythrocytes
The transcript variant reported to be impacted by the Fy- allele (DARC/ACKR1-B) is not the transcript affected in lymphoblast cells
Summary
The Duffy Antigen Receptor for Chemokines (DARC), recently renamed Atypical Chemokine Receptor 1 (ACKR1), expresses the red blood cell antigens that define the Duffy Blood Groups for which it was originally discovered [1, 2]. DARC/ACKR1 has been implicated to affect cancers as a pro-inflammatory cytokine receptor, in lung cancer etiology, BrCa progression by in vitro studies and allele-specific BrCa patient survival [12,13,14]. While these studies implicate DARC/ACKR1 in cancer processes, there are still lingering questions concerning how DARC/ACKR1 lends its chemokine binding capacity toward cancer progression. There is very little investigation of DARC/ACKR1 in regard to the complexity of gene product variants and their distinct role in biological outcomes of immune/inflammatory responses during tumorigenesis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
