Normal ABL1 kinase as tumor suppressor and therapeutic target in leukemia
正常 ABL1 激酶作为白血病的肿瘤抑制因子和治疗靶点
基本信息
- 批准号:9897628
- 负责人:
- 金额:$ 48.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:9q34ABL1 geneAcute Lymphocytic LeukemiaAcute leukemiaAdhesionsAllelesApoptosisAutophagocytosisB-LymphocytesBlast PhaseBloodBone Marrow CellsCRISPR screenCell AdhesionCell NucleusCell ProliferationCell SurvivalCellsChromosomal translocationChromosome 9Chromosome abnormalityChronicChronic Myeloid LeukemiaChronic-Phase Myeloid LeukemiaDNA DamageDNA RepairDataDatabasesDiseaseDrug usageFLT3 geneGene SilencingGeneticGenotoxic StressHandHematologic NeoplasmsHematopoieticHematopoietic stem cellsImatinibImidazolidinesInduction of ApoptosisJAK2 geneMalignant - descriptorMediatingMitochondriaModalityMusMyelogenousMyeloid CellsNUP214 geneNecrosisNuclearOncogenesOncogenicPathogenesisPharmaceutical PreparationsPhosphotransferasesPlayPost-Translational Protein ProcessingProteinsProto-Oncogene Proteins c-ablPublishingRegulationReportingRoleSignal PathwayT-Cell DevelopmentTestingTumor Suppressor ProteinsTyrosine Kinase InhibitorWorkXenograft procedurecell growthcell motilitychronic leukemiadiagnostic biomarkergenome-wideinterstitialleukemialeukemic stem cellleukemogenesismutantnovelnovel diagnosticsnovel therapeutic interventionpromoterresponsetherapeutic targettreatment response
项目摘要
Constitutively activated oncogenic mutants of the ABL1 tyrosine kinase play a central role in the pathogenesis of
acute and chronic leukemias. Activation usually occurs as a consequence of chromosomal translocations (BCR-
ABL1, TEL-ABL1 and others) or episomal amplification (NUP214-ABL1).
Leukemias expressing oncogenic forms of the ABL1 kinase usually contain the non-mutated allele encoding
normal ABL1 kinase which may play an important role in pathogenesis of disease and/or in response to treatment,
given its prominent role in regulation of cell motility, adhesion, autophagy, response to DNA damage, apoptosis and
proliferation. We recently reported that BCR-ABL1-Abl1-/- murine bone marrow cells generated highly aggressive
chronic myeloid leukemia-blast phase (CML-BP)-like disease in mice compared to less malignant CML-chronic
phase (CML-CP)-like disease from BCR-ABL1-Abl1+/+ cells. Additionally, loss of ABL1 stimulated proliferation and
dramatic expansion of BCR-ABL1 murine leukemia stem cells, arrested myeloid differentiation, inhibited genotoxic
stress-induced apoptosis, and facilitated accumulation of chromosomal aberrations. Moreover, we reported that in
the absence of ABL1, BCR-ABL1 cells displayed reduced sensitivity to tyrosine kinase inhibitors (TKIs) such as
imatinib; conversely allosteric stimulation of the ABL1 kinase enhanced anti-leukemia effect of TKIs in BCR-ABL1-
positive CML and BCR-ABL1-positive acute lymphoblastic leukemia (ALL).
We postulate that normal ABL1 is a tumor suppressor and therapeutic target in leukemias induced not only by
BCR-ABL1, but also by other oncogenes. To test these hypotheses we propose 3 specific aims.
Specific Aim #1. Identification of genetic aberrations benefiting from the loss of ABL1 to induce leukemia.
a) We will determine the role of ABL1 loss in leukemogenesis induced by chromosomal translocations identified in
the CGAP Mitelman database. b) We will perform genome-wide CRISPR screen to detect genetic aberrations
promoting malignant transformation of Abl1-/- hematopoietic cells, but not their Abl1+/+ counterparts.
Specific Aim #2. Mechanisms of ABL1-mediated tumor suppressor activity.
a) We will employ ABL1 mutants to determine if nuclear and/or cytoplasmic ABL1 is a tumor suppressor. b) We
will pinpoint upstream and downstream signaling pathways responsible for ABL1 tumor suppressor activities.
Specific Aim #3. ABL1 kinase as therapeutic target in leukemias.
a) We will determine if allosteric activator of ABL1 (DPH) also enhances anti-leukemia efficacy of TKIs targeting
FLT3(ITD) and JAK2(V617F) in primary AMLs/MPNs cells. b) We will test novel therapeutic approach combining
DPH + already approved drugs using primary leukemia xenografts carrying BCR-ABL1, FLT3(ITD) or JAK2(V617F).
c) We will test more potent ABL1 kinase activators.
This proposal may identify novel diagnostic marker (loss of ABL1) predisposing for malignant progression of
leukemia. Moreover, ABL1, when expressed may be a valid target for novel anti-leukemia modalities.
ABL 1酪氨酸激酶组成性激活的致癌突变体在肿瘤的发病机制中起着重要作用。
急性和慢性白血病。激活通常是由于染色体易位(BCR-1)而发生的。
ABL 1、TEL-ABL 1等)或附加型扩增(NUP 214-ABL 1)。
表达ABL 1激酶致癌形式的白血病通常含有编码ABL 1激酶的非突变等位基因。
正常ABL 1激酶,其可能在疾病的发病机制和/或对治疗的应答中起重要作用,
鉴于其在调节细胞运动性、粘附、自噬、对DNA损伤的应答、凋亡和凋亡中的突出作用,
增殖我们最近报道,BCR-ABL 1-ABL 1-/-小鼠骨髓细胞产生高度侵袭性的
与恶性程度较低的慢性粒细胞白血病(CML)相比,
BCR-ABL 1-BCR 1 +/+细胞的CML-CP样疾病。此外,ABL 1的缺失刺激了细胞增殖,
BCR-ABL 1小鼠白血病干细胞的急剧扩增,抑制髓样分化,抑制遗传毒性
应激诱导的细胞凋亡,并促进染色体畸变的积累。此外,我们报告说,在
在缺乏ABL 1的情况下,BCR-ABL 1细胞显示出对酪氨酸激酶抑制剂(TKI)的敏感性降低,
伊马替尼;相反,ABL 1激酶的变构刺激增强了TKI在BCR-ABL 1中的抗白血病作用。
CML阳性和BCR-ABL 1阳性急性淋巴细胞白血病(ALL)。
我们推测正常ABL 1是白血病的肿瘤抑制因子和治疗靶点,
BCR-ABL 1,但也通过其他癌基因。为了验证这些假设,我们提出了三个具体目标。
具体目标#1。鉴定受益于ABL 1缺失的遗传畸变以诱导白血病。
a)我们将确定ABL 1缺失在由染色体易位诱导的白血病发生中的作用,
援助最贫穷者协商组Mitelman数据库。B)我们将进行全基因组CRISPR筛查,以检测遗传畸变
促进β 1-/-造血细胞的恶性转化,但不促进其β 1 +/+对应物的恶性转化。
具体目标#2 ABL 1介导的肿瘤抑制活性的机制。
a)我们将使用ABL 1突变体来确定细胞核和/或细胞质ABL 1是否是肿瘤抑制因子。B)我们
将查明负责ABL 1肿瘤抑制活性的上游和下游信号通路。
具体目标#3 ABL 1激酶作为白血病的治疗靶点
a)我们将确定ABL 1的变构激活剂(DPH)是否也增强靶向TKI的抗白血病功效
原代AML/MPN细胞中的FLT 3(ITD)和JAK 2(V617 F)。B)我们将测试新的治疗方法,
DPH +已批准使用携带BCR-ABL 1、FLT 3(ITD)或JAK 2(V617 F)的原发性白血病异种移植物的药物。
c)我们将测试更有效的ABL 1激酶激活剂。
这一建议可能会发现新的诊断标志物(ABL 1的损失)诱发恶性进展,
白血病此外,ABL 1,表达时,可能是一个有效的目标,为新的抗白血病的方式。
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 }}
TOMASZ SKORSKI其他文献
TOMASZ SKORSKI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('TOMASZ SKORSKI', 18)}}的其他基金
Divergent Functions of ERK Substrate Binding Domains in Pathogenesis of Myeloproliferative Neoplasms
ERK 底物结合域在骨髓增生性肿瘤发病机制中的不同功能
- 批准号:
10719088 - 财政年份:2023
- 资助金额:
$ 48.67万 - 项目类别:
Oncogenic tyrosine kinases inhibitors abrogate DNA repair and sensitive leukemias to PARP inhibitors
致癌酪氨酸激酶抑制剂可消除 DNA 修复和对 PARP 抑制剂敏感的白血病
- 批准号:
10374000 - 财政年份:2020
- 资助金额:
$ 48.67万 - 项目类别:
MPN-inducing mutations as biomarkers of synthetic lethality
MPN 诱导突变作为合成致死率的生物标志物
- 批准号:
10444919 - 财政年份:2020
- 资助金额:
$ 48.67万 - 项目类别:
MPN-inducing mutations as biomarkers of synthetic lethality
MPN 诱导突变作为合成致死率的生物标志物
- 批准号:
10652426 - 财政年份:2020
- 资助金额:
$ 48.67万 - 项目类别:
Oncogenic tyrosine kinases inhibitors abrogate DNA repair and sensitive leukemias to PARP inhibitors
致癌酪氨酸激酶抑制剂可消除 DNA 修复和对 PARP 抑制剂敏感的白血病
- 批准号:
10608045 - 财政年份:2020
- 资助金额:
$ 48.67万 - 项目类别:
MPN-inducing mutations as biomarkers of synthetic lethality
MPN 诱导突变作为合成致死率的生物标志物
- 批准号:
10174883 - 财政年份:2020
- 资助金额:
$ 48.67万 - 项目类别:
Normal ABL1 kinase as tumor suppressor and therapeutic target in leukemia
正常 ABL1 激酶作为白血病的肿瘤抑制因子和治疗靶点
- 批准号:
9315519 - 财政年份:2017
- 资助金额:
$ 48.67万 - 项目类别:
Targeting DNA repair to eradicate TKi-refractory/resistant CML and Ph+ALL
靶向 DNA 修复以根除 TKi 难治性/耐药性 CML 和 Ph ALL
- 批准号:
9884207 - 财政年份:2014
- 资助金额:
$ 48.67万 - 项目类别:
Targeting DNA repair to eradicate TKI-refractory/resistant CML
靶向 DNA 修复以根除 TKI 难治性/耐药性 CML
- 批准号:
8702641 - 财政年份:2014
- 资助金额:
$ 48.67万 - 项目类别:
Targeting DNA repair to eradicate TKi-refractory/resistant CML and Ph+ALL
靶向 DNA 修复以根除 TKi 难治性/耐药性 CML 和 Ph ALL
- 批准号:
10357886 - 财政年份:2014
- 资助金额:
$ 48.67万 - 项目类别:
相似海外基金
Leukemogenicity of the RCSD1-ABL1 gene
RCSD1-ABL1 基因的致白血病性
- 批准号:
26461434 - 财政年份:2014
- 资助金额:
$ 48.67万 - 项目类别:
Grant-in-Aid for Scientific Research (C)














{{item.name}}会员




