Identification of RIOK2 as a master regulator of human blood cell development

ABSTRACT: Myelodysplastic syndromes (MDS) are a group of hematologic neoplasms in which the bone marrow fails to produce enough mature blood cells, leading to peripheral blood cytopenias and myeloproliferation1-3. The average survival time following diagnosis of MDS is 2.5 years4, owing to few treatment options5. Roughly 20-30% of MDS patients progress to acute myeloid leukemia6. Risks of allogeneic bone marrow transplants in elderly patients, together with a dearth of effective FDA-approved drugs, make it imperative to revisit the origins of hematopoietic differentiation defects underlying MDS to identify new druggable targets7-9. We recently reported that haploinsufficiency of the atypical kinase Riok2 (Right open reading frame kinase 2)10 in mice leads to anemia and MDS-associated phenotypes11. However, the underlying molecular mechanisms remain largely unexplored. Here we show that RIOK2 is a master transcription factor that not only drives erythroid lineage commitment, but simultaneously suppresses megakaryocytic and myeloid lineages in primary human stem and progenitor cells. Structural modeling, chromatin immunoprecipitation sequencing, ATAC-sequencing and structure-function domain deletion mutants revealed that RIOK2 activates or represses specific genetic programs in hematopoiesis via its previously unappreciated winged helix-turn-helix DNA-binding domain and two transactivation domains. Mechanistically, RIOK2 functions as a master regulator of hematopoietic lineage commitment by controlling the expression of key lineage-specific transcription factors, such as GATA1, GATA2, SPI1, RUNX3 and KLF1. We also show that GATA1 and RIOK2 function in a positive feedback loop to drive erythroid differentiation. These discoveries present novel therapeutic opportunities to correct hematopoietic differentiation defects in MDS, in the anemia of chronic diseases such as renal failure and inflammation, and in other bone marrow failure disorders.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Laurie Glimcher  

PROVIDER: MSV000088238 | MassIVE | Sat Oct 16 14:48:00 BST 2021

REPOSITORIES: MassIVE