The JAK2 46/1 haplotype influences PD-L1 expression

Abstract

Although described more than a decade ago, the mechanism by which the JAK2 46/1 haplotype increases the risk of developing myeloproliferative neoplasms (MPN) remains unexplained. Inflammation and immunity are linked to MPN development and thus could be relevant to the mechanism by which 46/1
mediates its effect. Here, we show that PD-L1 expression is elevated in 46/1 haplotype both in healthy carriers and CD34+ cells from MPN patients. Using circular chromosome conformation capture (4C-seq) we observe that PD-L1 and the neighboring PD-L2 loci physically interact with JAK2 in a manner that differs between 46/1 and non-risk haplotypes. Finally, we show through CRISPR/Cas9
genome editing that a non- coding region within JAK2 intron 2 influences both JAK2 and PD-L1 expression. We suggest that increased PD-L1 expression may be one of the mechanisms by which 46/1 leads to an increased inherited risk of developing MPN.

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Identifiers

ORCID for William J. Tapper: orcid.org/0000-0002-5896-1889

ORCID for Nicholas C.P. Cross: orcid.org/0000-0001-5481-2555

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