Pathophysiology of Adult T-cell leukemia/lymphoma
Pathophysiology of Adult T-cell leukemia/lymphoma
批准号:
10609828
负责人:
Utpal P Dave
金额:
$0.0万
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
项目状态:
未结题
起止时间:
2022-01-01 至 2025-12-31
关键词:
Acute T Cell LeukemiaAddressAdultAdult Precursor T Lymphoblastic LeukemiaAdult T-Cell Leukemia/LymphomaAffectApoptosisBHLH ProteinBindingBinding ProteinsBiochemicalBiological ModelsCaringCellsCharacteristicsChildClinicalComplexCytotoxic ChemotherapyDataDiagnosisDisease remissionEpidemiologyFunctional disorderGATA1 geneGrantGrowthHematopoietic stem cellsHumanImmunoblot AnalysisImmunophenotypingJAK1 geneKnowledgeLIM DomainLMO2 geneLYL1 geneLearningLentivirus VectorMacromolecular ComplexesMalignant NeoplasmsModelingOncogenesOncogenicPathway interactionsPatientsPatternPopulationPrognosisProliferatingPropertyProtein Binding DomainProteinsProteomicsRelapseRemission InductionResistanceRoleStructureT-LymphocyteTAL1 geneTechnologyTestingTherapeuticTranslatingVeteransagedchemotherapydrug candidatehigh riskhuman modelleukemialeukemia initiating cellleukemia/lymphomamalemilitary veteranmouse modelmutantnovelrelapse patientsrelapse riskresponseselective expressionsmall moleculestem cellsstem-like celltargeted treatmenttherapy resistanttranscriptome sequencingtranscriptomics
中文摘要
t细胞急性淋巴细胞白血病(T-ALL)是一种侵袭性癌症。成人T-ALL是常见的
英文摘要
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer in adult patients. Adult T-ALL is frequently
the Early T-cell Precursor (ETP-ALL) subtype that manifests with treatment-resistance and high risk of relapse.
The demographic of adult T-ALL matches that of young Veterans so this grant has the potential to impact the
diagnosis and care of this Veteran population. Like many aggressive human leukemias and lymphomas, T-ALL
can be put into remission by cytotoxic chemotherapy yet the majority of patients relapse. We have learned from
our studies that targeted therapies against mutant oncogenes stimulating proliferation, like JAK1/3, also induce
responses that are short lived. In these cancers, the high rate of complete remission followed by the high rate of
relapse is explained by the presence of treatment-resistant leukemia-initiating cells (LIC) that have hematopoietic
stem cell-like features. The LIC lie dormant and survive during chemotherapy and then expand after remission-
induction. Hence, targeting this LIC population is crucial to achieving cures. LIM domain Only-2 (LMO2) is a
major driver oncogene in T-ALL, where it confers stem cell characteristics upon normal T-cell progenitor cells.
Targeting LMO2-induced T-ALL LIC will involve targeting the LMO2 complex. Towards this end, we have
biochemically characterized the LMO2 complex to understand its structure and function. In preliminary data, we
show that LMO2’s oncogenic function requires it to act as part of a multisubunit macromolecular complex.
LMO2’s direct binding partners include the basic helix-loop-helix proteins, TAL1 or LYL1, and the GATA motif
binding proteins GATA1, 2, and 3. We discovered that LMO2’s ability to induce T-ALL is exquisitely dependent
upon another protein, LIM domain binding 1 (LDB1), to which LMO2 is constitutively bound. LDB1 has its own
interaction partners, namely the Single Stranded Binding Proteins SSBP1-4. Importantly, LMO2 complex
formation confers protein stability. In the course of our studies, we made observations that could hold the key to
better understanding LMO2’s induction of the LIC and to better targeting of the LMO2 complex. Although LMO2’s
induction of the LIC in mouse models has been extensively studied, this has not been translated to human cells.
We hypothesize that LIC properties are conferred by the LMO2 complex upon T-cell progenitor cells.
Furthermore, our proteomic studies reveal a panoply of paralogous proteins in the LMO2 complex but we do not
believe they are functionally equivalent. We hypothesize unique functional roles for the various paralogues of
the LMO2 complex, TAL1 v. LYL1, GATA factors 1-3, and SSBP factors 2 v. 3. We will investigate this in a novel
human modeling system. Lastly, we hypothesize that targeted therapy against LMO2 will involve perturbation of
the LMO2 complex. The Specific Aims of this grant will advance our understanding of how LMO2 functions and
how it may be targeted in these aggressive leukemias.
期刊论文(18)
专著(0)
科研奖励(0)
会议论文
登录
查看更多内容
DOI:
10.1038/s41467-020-18411-x
发表时间:
2020-09-21
期刊:
Nature communications
影响因子:
16.6
作者:
[Wu X, Niculite CM, Preda MB, Rossi A, Tebaldi T, Butoi E, White MK, Tudoran OM, Petrusca DN, Jannasch AS, Bone WP, Zong X, Fang F, Burlacu A, Paulsen MT, Hancock BA, Sandusky GE, Mitra S, Fishel ML, Buechlein A, Ivan C, Oikonomopoulos S, Gorospe M, Mosley A, Radovich M, Davé UP, Ragoussis J, Nephew KP, Mari B, McIntyre A, Konig H, Ljungman M, Cousminer DL, Macchi P, Ivan M]
通讯作者:
Ivan M
DOI:
10.1016/j.clml.2022.04.015
发表时间:
2022-04
期刊:
Clinical lymphoma, myeloma & leukemia
影响因子:
--
作者:
[Suheil Albert Atallah-Yunes;M. Robertson;Utpal P. Davé]
通讯作者:
Suheil Albert Atallah-Yunes;M. Robertson;Utpal P. Davé
DOI:
10.1016/j.jdcr.2020.08.041
发表时间:
2020-12
期刊:
JAAD case reports
影响因子:
--
作者:
[De la Sancha C, Burgin C, Warren S, Hoffmann K, Davé U, Nassiri M]
通讯作者:
Nassiri M
Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway.
DOI:
10.1172/jci.insight.163864
发表时间:
2023-05-08
期刊:
JCI INSIGHT
影响因子:
8
作者:
[Palam, Lakshmi Reddy, Ramdas, Baskar, Pickerell, Katelyn, Pasupuleti, Santhosh Kumar, Kanumuri, Rahul, Cesarano, Annamaria, Szymanski, Megan, Selman, Bryce, Dave, Utpal P., Sandusky, George, Perna, Fabiana, Paczesny, Sophie, Kapur, Reuben]
通讯作者:
Kapur, Reuben
DOI:
10.1158/1535-7163.mct-17-0141
发表时间:
2017-10
期刊:
Molecular cancer therapeutics
影响因子:
5.7
作者:
[Efimenko E, Davé UP, Lebedeva IV, Shen Y, Sanchez-Quintero MJ, Diolaiti D, Kung A, Lannutti BJ, Chen J, Realubit R, Niatsetskaya Z, Ten V, Karan C, Chen X, Califano A, Diacovo TG]
通讯作者:
Diacovo TG
共 9 条
Pathophysiology of Adult T-cell leukemia/lymphoma
-
批准号:10369933
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2022
-
负责人:Utpal P Dave
-
依托单位:
The Role of LMO2 in the Pathogenesis of T-cell Leukemia
-
批准号:9762024
-
项目类别:
-
资助金额:$34.97万
-
财政年份:2016
-
负责人:Utpal P Dave
-
依托单位:
Pathophysiology of Adult T-cell Leukemia/Lymphoma
-
批准号:8442075
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2012
-
负责人:Utpal P Dave
-
依托单位:
Pathophysiology of Adult T-cell Leukemia/Lymphoma
-
批准号:8762441
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2012
-
负责人:Utpal P Dave
-
依托单位:
Pathophysiology of Adult T-cell Leukemia/Lymphoma
-
批准号:9591306
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2012
-
负责人:Utpal P Dave
-
依托单位:
Pathophysiology of Adult T-cell Leukemia/Lymphoma
-
批准号:8963455
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2012
-
负责人:Utpal P Dave
-
依托单位:
Pathophysiology of Adult T-cell Leukemia/Lymphoma
-
批准号:10045553
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2012
-
负责人:Utpal P Dave
-
依托单位:
Pathophysiology of Adult T-cell Leukemia/Lymphoma
-
批准号:8624521
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2012
-
负责人:Utpal P Dave
-
依托单位:
Pathogenesis of SCID-X Gene Therapy - Induced Leukemias
-
批准号:7878805
-
项目类别:
-
资助金额:$12.72万
-
财政年份:2007
-
负责人:Utpal P Dave
-
依托单位:
Pathogenesis of SCID-X Gene Therapy - Induced Leukemias
-
批准号:8099490
-
项目类别:
-
资助金额:$12.77万
-
财政年份:2007
-
负责人:Utpal P Dave
-
依托单位:
Pathogenesis of SCID-X Gene Therapy - Induced Leukemias
-
批准号:7470023
-
项目类别:
-
资助金额:$12.61万
-
财政年份:2007
-
负责人:Utpal P Dave
-
依托单位:
Pathogenesis of SCID-X Gene Therapy - Induced Leukemias
-
批准号:7299365
-
项目类别:
-
资助金额:$12.56万
-
财政年份:2007
-
负责人:Utpal P Dave
-
依托单位:
Pathogenesis of SCID-X Gene Therapy - Induced Leukemias
-
批准号:7635819
-
项目类别:
-
资助金额:$12.66万
-
财政年份:2007
-
负责人:Utpal P Dave
-
依托单位:
海外基金