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

Nat Immunol. 2022 Jan;23(1):109-121. doi: 10.1038/s41590-021-01079-w. Epub 2021 Dec 22.


Anemia is a major comorbidity in aging, chronic kidney and inflammatory diseases, and hematologic malignancies. However, the transcriptomic networks governing hematopoietic differentiation in blood cell development remain incompletely defined. Here we report that the atypical kinase RIOK2 (right open reading frame kinase 2) is a master transcription factor (TF) that not only drives erythroid differentiation, but also simultaneously suppresses megakaryopoiesis and myelopoiesis in primary human stem and progenitor cells. Our study reveals the previously uncharacterized winged helix-turn-helix DNA-binding domain and two transactivation domains of RIOK2 that are critical to regulate key hematopoietic TFs GATA1, GATA2, SPI1, RUNX3 and KLF1. This establishes RIOK2 as an integral component of the transcriptional regulatory network governing human hematopoietic differentiation. Importantly, RIOK2 mRNA expression significantly correlates with these TFs and other hematopoietic genes in myelodysplastic syndromes, acute myeloid leukemia and chronic kidney disease. Further investigation of RIOK2-mediated transcriptional pathways should yield therapeutic approaches to correct defective hematopoiesis in hematologic disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Blood Cells / metabolism*
  • Cell Differentiation / physiology
  • Cell Line, Tumor
  • Cells, Cultured
  • Erythropoiesis / physiology
  • Gene Expression Regulation / physiology
  • HEK293 Cells
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • K562 Cells
  • Leukemia, Myeloid, Acute / metabolism
  • Myelodysplastic Syndromes / metabolism
  • Myelopoiesis / physiology
  • Protein Serine-Threonine Kinases / metabolism*
  • Transcription Factors / metabolism
  • Transcription, Genetic / physiology


  • Transcription Factors
  • Protein Serine-Threonine Kinases
  • RIOK2 protein, human