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

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.
组成型激活的ABL1酪氨酸激酶的致癌突变体在肿瘤的发病机制中起核心作用

项目成果

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TOMASZ SKORSKI其他文献

TOMASZ SKORSKI的其他文献

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{{ 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)
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