Multi-faceted Roles of an Atypical Kinase RIOK2 in Erythropoiesis and Myelodyplastic Syndromes
Multi-faceted Roles of an Atypical Kinase RIOK2 in Erythropoiesis and Myelodyplastic Syndromes
批准号:
10046930
负责人:
LAURIE Hollis GLIMCHER
金额:
$17.7万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-08-01 至 2021-07-31
关键词:
Acute Myelocytic LeukemiaAffectAgeAnemiaAntibodiesAplastic AnemiaAryl Hydrocarbon ReceptorBiogenesisBiological Response ModifiersBone MarrowBone Marrow CellsCD34 geneCD4 Positive T LymphocytesCell CycleCellsChromosome DeletionCombined Modality TherapyDataData SetDefectDevelopmentDiagnosisDiamondDominant-Negative MutationDysmyelopoietic SyndromesEmbryoErythroidErythropoiesisEtiologyExpression ProfilingFrequenciesFunctional disorderGenerationsGenesGeneticGenetic TranscriptionHematologic NeoplasmsHematopoiesisImmuneImmune TargetingImmune systemImmunobiologyImmunotherapyIndividualKnockout MiceKnowledgeLarge-Scale SequencingLeadLinkLiquid substanceMediatingMessenger RNAMolecularMusMutateMutationMyelogenousMyeloid CellsMyelopoiesisMyelosuppressionNeoplasmsOpen Reading FramesPathogenesisPathway interactionsPatientsPharmaceutical PreparationsPhosphotransferasesProductionProtein BiosynthesisProtein-Serine-Threonine KinasesProteomeQuality of lifeReading FramesReportingRibosomesRiskRoleS100A9 geneSamplingShwachman-Diamond syndrome Signal PathwayStem cell transplantSurvival RateSyndromeT-LymphocyteTestingTherapeuticUnited StatesUnited States Food and Drug Administrationbasecell agechromosome 5q losscomorbiditycytokinedesignefficacy testingerythroid differentiationimprovedimproved outcomeinterleukin-22lenalidomideloss of functionmRNA Expressionmouse modelnew therapeutic targetnoveloutcome forecastperipheral bloodprogenitorside effecttargeted treatmenttherapeutic evaluationtherapeutic targettranscriptometranscriptome sequencing
中文摘要
非典型激酶RIOK2在红细胞生成和骨髓增生异常综合征中的多方面作用
英文摘要
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 and anemia patients. Targeting IL-22 may encourage more effective immune-
based treatments that, either as single agent therapy or in combination with current therapies, will improve the
prognosis and quality of life of MDS patients.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Developing a pragmatic guide to implementing social risk referrals: A partnership between Caring Health Center (CHC) and the Implementation Science Center for Cancer
-
批准号:10822141
-
项目类别:
-
资助金额:$22.47万
-
财政年份:2023
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
Understanding the impact of an EHR-integrated hereditary cancer risk assessment application on patient-provider communication
-
批准号:10831167
-
项目类别:
-
资助金额:$10.0万
-
财政年份:2023
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
Real-World Molecularly Targeted Treatment Registry (MaTTeR): a Pilot Study to Enrich CCDI Data Utilizing Directed Electronic Medical Record (EMR) Extraction
-
批准号:10878384
-
项目类别:
-
资助金额:$49.59万
-
财政年份:2023
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
Repurposing Bruton's tyrosine kinase (BTK) inhibitors to reverse immunosuppression in high-grade serous ovarian cancer (HGSC)
-
批准号:10661823
-
项目类别:
-
资助金额:$8.9万
-
财政年份:2022
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
Repurposing Bruton's tyrosine kinase (BTK) inhibitors to reverse immunosuppression in high-grade serous ovarian cancer (HGSC)
-
批准号:10512441
-
项目类别:
-
资助金额:$8.9万
-
财政年份:2022
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
Novel Regulators of Bone Formation
-
批准号:8573484
-
项目类别:
-
资助金额:$21.58万
-
财政年份:2012
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
Schnurri-3 Inhibitors: specific inducers of adult bone formation
-
批准号:8259713
-
项目类别:
-
资助金额:$4.04万
-
财政年份:2011
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
VivaCT 40 Scanner
-
批准号:8052441
-
项目类别:
-
资助金额:$39.67万
-
财政年份:2011
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
Schnurri-3 Inhibitors: specific inducers of adult bone formation
-
批准号:8139368
-
项目类别:
-
资助金额:$4.04万
-
财政年份:2011
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
From Sugar to Fat: How Transcription Factor XBP1 Regulates Hepatic Lipogenesis
-
批准号:8308665
-
项目类别:
-
资助金额:$33.59万
-
财政年份:2010
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
Transcriptional Regulation of the Immune Response
-
批准号:8092054
-
项目类别:
-
资助金额:$22.94万
-
财政年份:2010
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
From Sugar to Fat: How Transcription Factor XBP1 Regulates Hepatic Lipogenesis
-
批准号:8725136
-
项目类别:
-
资助金额:$34.82万
-
财政年份:2010
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
Novel Regulators of Bone Formation
-
批准号:8099282
-
项目类别:
-
资助金额:$8.73万
-
财政年份:2010
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
From Sugar to Fat: How Transcription Factor XBP1 Regulates Hepatic Lipogenesis
-
批准号:8143301
-
项目类别:
-
资助金额:$33.59万
-
财政年份:2010
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
From Sugar to Fat: How Transcription Factor XBP1 Regulates Hepatic Lipogenesis
-
批准号:8513981
-
项目类别:
-
资助金额:$33.6万
-
财政年份:2010
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
T-bet and the Th1/Th17 balance in Acute HIV infection
-
批准号:8134863
-
项目类别:
-
资助金额:$23.98万
-
财政年份:2010
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
From Sugar to Fat: How the Transcription Factor XBP1 Regulates Hepatic Lipogenesi
-
批准号:7983329
-
项目类别:
-
资助金额:$36.79万
-
财政年份:2010
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
T-bet and the Th1/Th17 balance in Acute HIV infection
-
批准号:7840135
-
项目类别:
-
资助金额:$20.19万
-
财政年份:2010
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
T-bet and Tumor Immunity
-
批准号:7909161
-
项目类别:
-
资助金额:$31.77万
-
财政年份:2009
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
Novel Regulators of Bone Formation
-
批准号:8105521
-
项目类别:
-
资助金额:$26.08万
-
财政年份:2008
-
负责人:LAURIE Hollis GLIMCHER
-
依托单位:
海外基金