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

Ghosh, Shreya; Raundhal, Mahesh; Myers, Samuel A.; Carr, Steven A.; Chen, Xi; Petsko, Gregory A.; Glimcher, Laurie H.

doi:10.1038/s41590-021-01079-w

Cited by 17 publications

(14 citation statements)

References 50 publications

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“…KLF1 control elements have been clearly established in vitro 33 and in vivo 34 – 37 . These studies have delineated a relatively simple layout of a short (~ 1 kB) region adjacent to the transcriptional start site containing erythroid-specific hypersensitive (EHS1 and 2) upstream enhancer elements that bind hematopoietic general and tissue-restricted regulators 38 – 41 and respond to BMP4 signaling. Coupled to this, an enhancer element in intron 1 plays a critical role in establishing its maximal expression level 37 .…”

Section: Introductionmentioning

confidence: 99%

Identification of a genomic DNA sequence that quantitatively modulates KLF1 transcription factor expression in differentiating human hematopoietic cells

Gnanapragasam

Planutis

Glassberg

et al. 2023

Sci Rep

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The onset of erythropoiesis is under strict developmental control, with direct and indirect inputs influencing its derivation from the hematopoietic stem cell. A major regulator of this transition is KLF1/EKLF, a zinc finger transcription factor that plays a global role in all aspects of erythropoiesis. Here, we have identified a short, conserved enhancer element in KLF1 intron 1 that is important for establishing optimal levels of KLF1 in mouse and human cells. Chromatin accessibility of this site exhibits cell-type specificity and is under developmental control during the differentiation of human CD34+ cells towards the erythroid lineage. This site binds GATA1, SMAD1, TAL1, and ETV6. In vivo editing of this region in cell lines and primary cells reduces KLF1 expression quantitatively. However, we find that, similar to observations seen in pedigrees of families with KLF1 mutations, downstream effects are variable, suggesting that the global architecture of the site is buffered towards keeping the KLF1 genetic region in an active state. We propose that modification of intron 1 in both alleles is not equivalent to complete loss of function of one allele.

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Section: Introductionmentioning

confidence: 99%

Identification of a genomic DNA sequence that quantitatively modulates KLF1 transcription factor expression in differentiating human hematopoietic cells

Gnanapragasam

Planutis

Glassberg

et al. 2023

Sci Rep

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“…6 Further studies also suggest that RIOK2 plays important roles in the mitotic progression, migration and human blood cell differentiation process through the PLK1, mTOR/AKT and GATA1 signal pathway. 7–11…”

Section: Introductionmentioning

confidence: 99%

Exploration of tricyclic heterocycles as core structures for RIOK2 inhibitors

Xiong¹,

Yu²,

Ma³

et al. 2023

RSC Med. Chem.

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“…Depletion of RIOK2 or loss of catalytic activity results in defects in recycling of processing factors, thereby preventing maturation . A recent study also identified RIOK2 as a master transcription factor (TF) governing human blood cell differentiation by regulating key hematopoietic TFs including GATA1, GATA2, SPI1, RUNX3, and KLF1 …”

Section: Introductionmentioning

confidence: 99%

“…8 A recent study also identified RIOK2 as a master transcription factor (TF) governing human blood cell differentiation by regulating key hematopoietic TFs including GATA1, GATA2, SPI1, RUNX3, and KLF1. 10 RIOK2 has been implicated in a variety of cancers in which high RIOK2 expression was correlated with poor outcome. 11 These include colorectal carcinoma, melanoma, nonsmall-cell lung carcinoma, and glioblastoma.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of 8-(6-Methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ211) as a Highly Potent and Selective RIOK2 Inhibitor

Ouyang

Zhu

et al. 2022

J. Med. Chem.

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RIOK2 is an atypical kinase implicated in multiple human cancers. Although recent studies establish the role of RIOK2 in ribosome maturation and cell cycle progression, its biological functions remain poorly elucidated, hindering the potential to explore RIOK2 as a therapeutic target. Here, we report the discovery of CQ211, the most potent and selective RIOK2 inhibitor reported so far. CQ211 displays a high binding affinity (K d = 6.1 nM) and shows excellent selectivity to RIOK2 in both enzymatic and cellular studies. It also exhibits potent proliferation inhibition activity against multiple cancer cell lines and demonstrates promising in vivo efficacy in mouse xenograft models. The crystal structure of RIOK2-CQ211 sheds light on the molecular mechanism of inhibition and informs the subsequent optimization. The study provides a cell-active chemical probe for verifying RIOK2 functions, which may also serve as a leading molecule in the development of therapeutic RIOK2 inhibitors.

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

Cited by 17 publications

References 50 publications

Identification of a genomic DNA sequence that quantitatively modulates KLF1 transcription factor expression in differentiating human hematopoietic cells

Identification of a genomic DNA sequence that quantitatively modulates KLF1 transcription factor expression in differentiating human hematopoietic cells

Exploration of tricyclic heterocycles as core structures for RIOK2 inhibitors

Discovery of 8-(6-Methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ211) as a Highly Potent and Selective RIOK2 Inhibitor

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