Defining the Mechanism of Genome Rearrangements in Ph-Like ALL to Determine Predictive Markers in High-Risk Hispanic Populations
定义 Ph 样 ALL 基因组重排机制以确定高危西班牙裔人群的预测标记
基本信息
- 批准号:10737875
- 负责人:
- 金额:$ 7.74万
- 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:2022-02-14 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:Acute Lymphocytic LeukemiaAddressAdolescent and Young AdultAdvocateAffectAutomobile DrivingB lymphoid malignancyB-Cell Acute Lymphoblastic LeukemiaB-LymphocytesBiological AssayCRISPR/Cas technologyCaliforniaCatchment AreaCellsChromosomal translocationClinicalCollecting CellCommunitiesComparative StudyComprehensive Cancer CenterCytokine ReceptorsCytosineDNA Double Strand BreakDNA MethylationDNA RepairDataDeaminationDiagnosisDiagnosticDiseaseDisease remissionDisparityDoxycyclineEarly DiagnosisEarly InterventionEnzyme ActivationEpigenetic ProcessEthnic OriginEtiologyFosteringGene ExpressionGeneral PopulationGenesGeneticGenomeGenomic InstabilityGenomicsGoalsHealthHeavy-Chain ImmunoglobulinsHispanicHispanic PopulationsHumanIGH@ gene clusterIncidenceKnowledgeLatino PopulationLinkMapsMethodsMethylationMissionModificationMolecularMutationNot Hispanic or LatinoOncogenesPatientsPhiladelphia ChromosomePopulationPredisposing FactorPrevalencePreventionPrevention strategyPreventive MedicineProcessPublic HealthRecurrent diseaseRegulationResearchRiskRoleSampling StudiesSiteSurvival RateTechniquesTestingTimeUnited States National Institutes of HealthWhole BloodWorkactivation-induced cytidine deaminasebcr-abl Fusion Proteinsbisulfite sequencingcancer health disparitycancer riskcommunity livingdigitaleffective therapyexperimental studygenome-widehealth disparityhigh riskhispanic communityhuman diseaseimprintimprovedimproved outcomeindividualized preventioninnovationlectureslentiviral integrationmeetingsmethylation patternmortalitynovelnovel diagnosticsoverexpressionpersonalized medicinepersonalized predictionspredictive markerrelapse riskrepairedstemtreatment comparisontreatment response
项目摘要
PROJECT SUMMARY/ABSTRACT
Philadelphia chromosome-like B cell acute lymphoblastic leukemia (Ph-like ALL) is an ALL subtype that
disproportionately affects the Hispanic community and is characterized as having a poor response to therapy,
a high risk of relapse, and a peak onset in adolescents and young adults. While lacking a BCR-ABL fusion,
nearly 65% of Ph-like ALL cases carry a rearrangement in the cytokine receptor-like factor 2 (CRLF2) gene,
the most common being a chromosomal translocation with the immunoglobulin heavy chain locus (CRLF2-IgH)
resulting in overexpression of CRLF2 and low survival. One comparative study found that Ph-like ALL occurred
in 68% of Hispanics versus 23% of Whites and of those, 78% of Hispanics had disease associated with CRLF2
rearrangements compared to 22% of Whites, indicating a clear cancer disparity. The long-term goal is to
develop predictive diagnostics based upon a patient’s genetic background to address cancer disparities. The
overall objectives for this proposal are to leverage genetic and molecular expertise on the etiology of B cell
malignancies to determine the mechanism underlying CRLF2-IgH formation and determine how changing
levels of B cell-specific factors and epigenetic imprinting predispose Hispanics to this translocation and thus
Ph-like ALL. The central hypothesis is that DNA double-strand breaks (DSBs) leading to CRLF2-IgH
translocations result from a mechanism involving activation-induced cytidine deaminase (AID) and DNA
methylation and that differential regulation of these processes in Hispanics is driving the cancer disparity. The
rationale for this project stems from results showing that CRLF2 DSBs resulting in CRLF2-IgH translocations
are highly enriched in a 311 bp cluster region. DSBs within this cluster occur at motifs recognized by AID and
these motifs contain CpG sequences that are also sites of DNA methylation. Evidence shows that meCT
deamination is more detrimental that CU deamination and more likely to result in DSBs. Determining if
aberrant AID expression and changing DNA methylation patterns account for increased CRLF2-IgH formation
in Hispanics is critical in addressing the Ph-like ALL disparity and will be tested through three specific aims: 1)
Define the molecular mechanism of CRLF2-IgH formation; 2) Determine genetic and epigenetic factors
underlying Ph-like ALL disparities in Hispanics; and 3) Develop a molecular assay to detect CRLF2-IgH
translocations and compare treatment response in Hispanics and non-Hispanics. The innovative aspects of
this work are identification of a 311 bp DSB cluster associated with CRLF2 instability, application of new
molecular and genomic techniques in human cells to address the etiology of Ph-like ALL, and the use of
patient material from the UCI comprehensive cancer center that serves a large Hispanic population. This work
is significant as it will address a major cancer health disparity in the Hispanic community and develops a novel
diagnostic for early detection of new or relapsed disease while at the same time unravelling a molecular
mechanism that is not only relevant to Ph-like ALL, but also to several additional B cell malignancies.
项目摘要/摘要
费城染色体样B细胞急性淋巴细胞白血病(Ph-like ALL)是一种ALL亚型
对西班牙裔社区的影响不成比例,并被认为对治疗反应不佳,
复发风险高,青少年和青壮年发病高峰期。虽然缺乏BCR-ABL融合,
近65%的Ph样ALL病例携带细胞因子受体样因子2(CRLF2)基因重排,
最常见的是带有免疫球蛋白重链基因的染色体易位(CRLF2-IgH)
导致CRLF2过度表达,存活率低。一项比较研究发现,类Ph都发生在
在68%的西班牙裔和23%的白人中,78%的拉美裔有与CRLF2相关的疾病
相比之下,白人的这一比例为22%,显示出明显的癌症差异。长期目标是
根据患者的遗传背景开发预测性诊断,以解决癌症差异。这个
这项提案的总体目标是利用B细胞病因学方面的遗传和分子专业知识
恶性肿瘤以确定CRLF2-IgH形成的机制并确定如何改变
B细胞特异性因子的水平和表观遗传印记使拉美裔人容易发生这种易位,因此
像所有人一样。中心假设是DNA双链断裂(DSB)导致CRLF2-IgH
易位是由激活诱导的胞苷脱氨酶(AID)和DNA引起的
甲基化和拉美裔人对这些过程的不同调控是导致癌症差异的原因。这个
这个项目的基本原理源于结果表明CRLF2 DSB导致CRLF2-IGH易位
在311个碱基团簇区高度富集区。该簇中的DSB出现在由AID识别的基序和
这些基序包含CpG序列,这些序列也是DNA甲基化的位点。有证据表明,MECT
脱氨基比C--U脱氨基更有害,更有可能导致DSB。确定是否
异常的AID表达和DNA甲基化模式变化是CRLF2-IgH形成增加的原因
在拉美裔美国人中是解决Ph式所有差异的关键,并将通过三个具体目标进行测试:1)
明确CRLF2-IgH形成的分子机制;2)确定遗传和表观遗传因素
3)建立检测CRLF2-IgH的分子检测方法
并比较拉美裔和非拉美裔患者的治疗反应。的创新方面
这项工作是鉴定与CRLF2不稳定性有关的311个碱基的DSB星团,新的应用
人类细胞的分子和基因组技术,以解决类Ph ALL的病因学,并使用
患者材料来自UCI综合癌症中心,该中心服务于大量西班牙裔人口。这部作品
意义重大,因为它将解决拉美裔社区的主要癌症健康差距,并开发一种新的
早期诊断新的或复发的疾病,同时解开一种分子
这一机制不仅与类Ph ALL有关,而且还与其他几种B细胞恶性肿瘤有关。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Nicholas Pannunzio其他文献
Nicholas Pannunzio的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Nicholas Pannunzio', 18)}}的其他基金
Defining the Mechanism of Genome Rearrangements in Ph-Like ALL to Determine Predictive Markers in High-Risk Hispanic Populations
定义 Ph 样 ALL 基因组重排机制以确定高危西班牙裔人群的预测标记
- 批准号:
10347835 - 财政年份:2022
- 资助金额:
$ 7.74万 - 项目类别:
Effect of dietary, pharmacological, and genetic topoisomerase ablation on Ph-like ALL risk in Hispanics
饮食、药物和遗传拓扑异构酶消融对西班牙裔 Ph 样 ALL 风险的影响
- 批准号:
10598405 - 财政年份:2022
- 资助金额:
$ 7.74万 - 项目类别:
Rapid detection of CRLF2 rearrangements in Hispanic Ph-like ALL patients to access diagnosis and relapse
快速检测西班牙裔 Ph 样 ALL 患者中的 CRLF2 重排以进行诊断和复发
- 批准号:
10598411 - 财政年份:2022
- 资助金额:
$ 7.74万 - 项目类别:
Defining the Mechanism of Genome Rearrangements in Ph-Like ALL to Determine Predictive Markers in High-Risk Hispanic Populations
定义 Ph 样 ALL 基因组重排机制以确定高危西班牙裔人群的预测标记
- 批准号:
10570932 - 财政年份:2022
- 资助金额:
$ 7.74万 - 项目类别:
Defining the Mechanism of Genome Rearrangements in Ph-Like ALL to Determine Predictive Markers in High-Risk Hispanic Populations
定义 Ph 样 ALL 基因组重排机制以确定高危西班牙裔人群的预测标记
- 批准号:
10737876 - 财政年份:2022
- 资助金额:
$ 7.74万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 7.74万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 7.74万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 7.74万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 7.74万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 7.74万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 7.74万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 7.74万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 7.74万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 7.74万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 7.74万 - 项目类别:
Research Grant