The effect of cohesin mutations on HLA-class II expression in the myeloid leukemia of Down syndrome.
Boucher AC., Rosikiewicz W., Cotton A., Broadhurst AL., Ling T., Vadlamudi R., Bremm M., Schmell A-L., Konada L., Niederkorn M., Murray JD., Li Y., Narina S., Inglott S., Roy A., Ancliff P., Tirtakusuma R., Ma J., Walsh MP., Klco JM., Thomas PG., Wang Y., Tsirigos A., Cheng Y., Xu B., Ma X., Meshinchi S., Wagenblast E., Pruett-Miller SM., Rao S., Wu G., Olufadi Y., Kang G., Tothova Z., Taub JW., Ge Y., Vyas P., Klusmann J-H., Crispino JD.
Children with Down syndrome (DS) frequently develop transient abnormal myelopoiesis that can evolve to the myeloid leukemia of DS (ML-DS). TAM spontaneously resolves in most cases but progresses to ML-DS with additional mutations, most commonly in the cohesin complex. However, the mechanisms by which these alterations promote leukemia are unknown. We leveraged the RAD21-mutant CMY cell line and RAD21-corrected CMY isogenic clones, as well as patient data, to investigate the effect of cohesin mutations during leukemia progression. RNA-sequencing revealed that HLA-class II genes were significantly down-regulated with cohesin mutations. Furthermore, HLA-DR was found to be lower in ML-DS relative to TAM, and these decreased levels were associated with increased risk of leukemia progression. Multi-omic analyses revealed that haploinsufficiency of RAD21 altered chromatin accessibility and impaired the occupancy of GATA1s and CIITA, the master regulator of HLA-class II gene expression. Chromatin binding of CIITA was increased with RAD21 correction, providing a mechanism by which restoration of cohesin improves HLA-class II expression. Finally, decreased levels of RAD21 or STAG2 expression in other subtypes of AML also exhibited reduced expression of HLA-class II genes. Thus, cohesin may contribute to leukemia by altering HLA-class II gene expression.