Dissecting innate immune signaling in pre-leukemia evolution
剖析白血病前期进化中的先天免疫信号
基本信息
- 批准号:10462192
- 负责人:
- 金额:$ 65.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-04 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:AcetylationAcute Myelocytic LeukemiaAffectAgingAgonistApplications GrantsBindingBiological AssayCell physiologyCellsClinicalDataDevelopmentDiseaseDysmyelopoietic SyndromesEvolutionGene ExpressionGene Expression ProfilingGeneticGenetic ModelsGoalsHematopoiesisHematopoieticHematopoietic NeoplasmsHematopoietic stem cellsHumanHypermethylationImmune signalingIndividualLinkLysineMalignant - descriptorMediatingMessenger RNAModelingModificationMolecularMusMutateMutationMyeloid LeukemiaMyeloproliferative diseaseOncogenicOutcomePathway interactionsPatientsPhenotypePost-Translational Protein ProcessingPreleukemiaProteinsProteomicsRNA SplicingRNA interference screenRegulationRiskRoleSignal TransductionTRAF6 geneTherapeuticToll-like receptorsTumor Suppressor ProteinsUbiquitinUbiquitinationacute myeloid leukemia cellbasedisorder subtypehuman diseasehuman stem cellsimprovedin vivoinnate immune pathwaysinsightleukemialoss of functionmouse modelnovelpromoterprotein expressionself-renewalsmall hairpin RNAstem cell functionstem cellstranscriptometumorubiquitin-protein ligase
项目摘要
Abstract
Clonal hematopoiesis (CH) is an aging associated condition characterized by the clonal outgrowth of
mutated pre-leukemic cells. Although individuals with CH are healthy, they are at an increased risk of
developing hematopoietic malignancies. To identify cooperating molecular alterations required for
malignant transformation of clonal pre-leukemic HSPC, we performed an in vivo shRNA screen and found
that shRNAs targeting Traf6 were overwhelmingly enriched in following transformation to overt myeloid
leukemias. TRAF6 is an ubiquitin E3 ligase that synthesizes Lysine (K) 63-linked ubiquitin chains on
substrates leading to Toll-like receptor (TLR) superfamily pathway activation. In support of our in vivo
shRNA screen, promoter hypermethylation and reduced expression of TRAF6 is observed in subsets of
myeloid malignancy patients, including ~40-50% of acute myeloid leukemia (AML). Moreover, our
preliminary data shows that deletion of Traf6 in pre-leukemic Tet2-deficient HSPC results in an aggressive
myeloid neoplasm in part through a novel MYC-dependent mechanism. Based on our findings, we
hypothesize that loss of TRAF6 drives subsets of genetically-defined myeloid malignancies, specifically
via a novel post-translational modification of MYC resulting in its activation. The objectives of the proposal
are to uncover the molecular and cellular basis of TRAF6 deletion on pre-leukemic HSPC function with the
long-term goal of uncovering improved therapeutic approaches by investigating the consequences of
TRAF6 deletion in models of CH and on leukemia development (Aim 1), identifying the molecular basis of
the tumor suppressor-like function of TRAF6 in AML (Aim 2), and evaluating the oncogenic potential of a
novel TRAF6-dependent MYC post-translational modification (Aim 3). These studies are highly significant
as they will provide critical insight into the progression of pre-leukemic states to overt leukemia as a result
of subverting select innate immune pathways, describe a novel disease-modifying role of TLR-TRAF6, and
reveal an unreported mechanism of MYC regulation. These studies have direct translational implications
and fill an unmet clinical need for genetically- and phenotypically-defined subtypes of AML/MPN.
摘要
项目成果
期刊论文数量(0)
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Iannis Aifantis其他文献
Iannis Aifantis的其他文献
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{{ truncateString('Iannis Aifantis', 18)}}的其他基金
The role of inflammation in the regulation of immune response in acute myeloid leukemia
炎症在急性髓系白血病免疫反应调节中的作用
- 批准号:
10729281 - 财政年份:2023
- 资助金额:
$ 65.3万 - 项目类别:
Dissecting innate immune signaling in pre-leukemia evolution
剖析白血病前期进化中的先天免疫信号
- 批准号:
10584536 - 财政年份:2022
- 资助金额:
$ 65.3万 - 项目类别:
mRNA stability and its impact on hematopoiesis and acute leukemia
mRNA稳定性及其对造血和急性白血病的影响
- 批准号:
10339742 - 财政年份:2022
- 资助金额:
$ 65.3万 - 项目类别:
mRNA stability and its impact on hematopoiesis and acute leukemia
mRNA稳定性及其对造血和急性白血病的影响
- 批准号:
10543125 - 财政年份:2022
- 资助金额:
$ 65.3万 - 项目类别:
Regulation of emergency hematopoiesis by the ubiquitin-proteasome system
泛素-蛋白酶体系统对紧急造血的调节
- 批准号:
10279596 - 财政年份:2021
- 资助金额:
$ 65.3万 - 项目类别:
Regulation of emergency hematopoiesis by the ubiquitin-proteasome system
泛素-蛋白酶体系统对紧急造血的调节
- 批准号:
10634676 - 财政年份:2021
- 资助金额:
$ 65.3万 - 项目类别:
Project 3: Oncogenic triggers and their influence on 3D chromosomal architecture
项目 3:致癌触发因素及其对 3D 染色体结构的影响
- 批准号:
10652283 - 财政年份:2019
- 资助金额:
$ 65.3万 - 项目类别:
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