Cohesin mutations suppress HLA class II gene expression to promote immune evasion during the progression to acute leukemia in children with Down syndrome. [RNA-Seq]

Children with Down syndrome have a 150-fold increased risk of developing the myeloid leukemia of Down syndrome (ML-DS). ML-DS is preceded by transient abnormal myelopoiesis (TAM), which spontaneously resolves in most cases but progresses to AML with additional mutations most commonly in the cohesin complex or signaling genes. However, the mechanisms by which these alterations promote leukemia are unknown. Here, we leveraged isogenic cell lines and patient data to investigate the role of cohesin mutations in leukemia progression. Multi-omic analyses revealed that haploinsufficiency of the cohesin complex suppresses the occupancy of CIITA at HLA class II loci, leading to a reduction in HLA Class II gene expression. Surface levels of HLA-DR are lower in ML-DS relative to TAM and these decreased levels are associated with an increased risk of TAM progression. Of note, a decrease in HLA-Class II gene expression is also a feature of non-DS AML with reduced expression of cohesin family members. These data suggest that unlike TAM, ML-DS blasts may evade the immune system by reduced HLA class II expression, providing a new model for leukemia progression in DS.