# Multi-faceted Roles of an Atypical Kinase RIOK2 in Erythropoiesis and Myelodyplastic Syndromes

> **NIH NIH R03** · DANA-FARBER CANCER INST · 2020 · $177,000

## Abstract

Multi-faceted Roles of an Atypical Kinase RIOK2 in Erythropoiesis and Myelodysplastic Syndromes
Project Summary
Myelodysplastic syndromes (MDS) are the most commonly diagnosed neoplasms in the United States with a
dismal survival rate. Furthermore, 1 in every 4 MDS patients is at risk of developing Acute Myeloid Leukemia
(AML), a devastating hematologic malignancy of myeloid cells. The median age of MDS diagnosis is 60 years,
thus making the only cure, stem cell transplantation unlikely in an older demographic with significant associated
co-morbidities. Current therapies using lenalidomide and hypomethylating agents are effective in a subset of
MDS patients but are also associated with side effects such as myelosuppression. Though our understanding of
the etiology of MDS has increased substantially in the past decade, the role of the immune system in MDS
pathogenesis is still greatly under explored. Thus, treatments targeting immune mediators have not been
therapeutically tested in MDS.
Based on our preliminary studies of a mouse model of haploinsufficient Riok2 expression (Riok2+/-) and MDS
patient samples, we have identified a link between Riok2 haploinsufficiency-mediated myelodysplasia and
induction of the immune cell-derived cytokine IL-22. Our data show that Riok2 haploinsufficiency has a direct
negative effect on erythroid progenitor differentiation and an indirect effect by inducing erythropoiesis-
suppressive IL-22 from T cells. Additionally, Riok2 haploinsufficiency-mediated cell cycle changes lead to
increased proliferation of myeloid cells. Importantly, RIOK2 mRNA expression is decreased in bone marrow cells
from MDS patients as compared to healthy controls. We have also identified one dominant negative and 5 loss
of function RIOK2 mutations that negatively impact erythropoiesis. Haploinsufficient deletion of Il22 in Riok2+/-
mice reversed the erythroid differentiation defect. Our study is the first to identify the critical function of Riok2 in
regulating erythropoiesis as well as the immune system, both synergistically leading to myelodysplasia.
In this proposal, we aim to mechanistically unravel the critical role of Riok2 and IL-22 in MDS and test the efficacy
of IL-22 inhibition on alleviation of the anemia and myelodysplasia seen in MDS. We will assess in detail how
loss or mutation of RIOK2 affects ribosome biogenesis, erythropoiesis, myelopoiesis, and IL-22 production.
Furthermore, we will also test whether IL-22 inhibition in Riok2+/- mice is a therapeutic strategy to alleviate the
anemia and myelodysplasia seen in MDS. Moreover, the high-throughput transcriptome and proteome analyses
of this novel mouse model of Riok2 haploinsufficiency-mediated MDS proposed here are expected to reveal
additional therapeutic targets, immune as well as non-immune, that can potentially be targeted for MDS
treatment. This knowledge should pave the way for devising a new generation of therapies that will improve the
outcome of disease for MDS, AML...

## Key facts

- **NIH application ID:** 10046930
- **Project number:** 1R03HL156574-01
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** LAURIE Hollis GLIMCHER
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $177,000
- **Award type:** 1
- **Project period:** 2020-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10046930

## Citation

> US National Institutes of Health, RePORTER application 10046930, Multi-faceted Roles of an Atypical Kinase RIOK2 in Erythropoiesis and Myelodyplastic Syndromes (1R03HL156574-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10046930. Licensed CC0.

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