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：
TOMASZ SKORSKI
金额：
$ 48.67万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
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：
https://reporter.nih.gov/project-details/9897628
关键词：
9q34 ABL1 gene Acute Lymphocytic Leukemia Acute leukemia Adhesions Alleles Apoptosis Autophagocytosis B-Lymphocytes Blast Phase Blood Bone Marrow Cells CRISPR screen Cell Adhesion Cell Nucleus Cell Proliferation Cell Survival Cells Chromosomal translocation Chromosome 9 Chromosome abnormality Chronic Chronic Myeloid Leukemia Chronic-Phase Myeloid Leukemia DNA Damage DNA Repair Data Databases Disease Drug usage FLT3 gene Gene Silencing Genetic Genotoxic Stress Hand Hematologic Neoplasms Hematopoietic Hematopoietic stem cells Imatinib Imidazolidines Induction of Apoptosis JAK2 gene Malignant - descriptor Mediating Mitochondria Modality Mus Myelogenous Myeloid Cells NUP214 gene Necrosis Nuclear Oncogenes Oncogenic Pathogenesis Pharmaceutical Preparations Phosphotransferases Play Post-Translational Protein Processing Proteins Proto-Oncogene Proteins c-abl Publishing Regulation Reporting Role Signal Pathway T-Cell Development Testing Tumor Suppressor Proteins Tyrosine Kinase Inhibitor Work Xenograft procedure cell growth cell motility chronic leukemia diagnostic biomarker genome-wide interstitial leukemia leukemic stem cell leukemogenesis mutant novel novel diagnostics novel therapeutic intervention promoter response therapeutic target treatment 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.

ABL1 酪氨酸激酶的组成型激活致癌突变体在癌症的发病机制中发挥着核心作用急性和慢性白血病。激活通常是由于染色体易位（BCR- ABL1、TEL-ABL1 等）或附加型扩增 (NUP214-ABL1)。表达 ABL1 激酶致癌形式的白血病通常包含编码非突变的等位基因正常的 ABL1 激酶可能在疾病的发病机制和/或治疗反应中发挥重要作用，鉴于其在调节细胞运动、粘附、自噬、DNA 损伤反应、细胞凋亡和增殖。我们最近报道 BCR-ABL1-Abl1-/- 小鼠骨髓细胞产生高度侵袭性与恶性程度较低的 CML 慢性相比，小鼠慢性粒细胞白血病急变期 (CML-BP) 样疾病来自 BCR-ABL1-Abl1+/+ 细胞的阶段 (CML-CP) 样疾病。此外，ABL1 的缺失会刺激增殖和 BCR-ABL1 小鼠白血病干细胞的显着扩增，抑制骨髓分化，抑制基因毒性应激诱导细胞凋亡，并促进染色体畸变的积累。此外，我们报道称，在由于缺乏 ABL1，BCR-ABL1 细胞对酪氨酸激酶抑制剂 (TKI) 的敏感性降低，例如伊马替尼；相反，ABL1 激酶的变构刺激增强了 TKI 在 BCR-ABL1- 中的抗白血病作用阳性 CML 和 BCR-ABL1 阳性急性淋巴细胞白血病 (ALL)。我们假设正常的 ABL1 不仅是由以下因素引起的白血病的肿瘤抑制因子和治疗靶点 BCR-ABL1，也受其他癌基因影响。为了检验这些假设，我们提出了 3 个具体目标。具体目标#1。鉴定因 ABL1 缺失而诱发白血病的遗传畸变。 a) 我们将确定 ABL1 缺失在由染色体易位诱导的白血病发生中的作用 CGAP Mitelman 数据库。 b) 我们将进行全基因组 CRISPR 筛选以检测遗传畸变促进 Abl1-/- 造血细胞的恶性转化，但不促进 Abl1+/+ 造血细胞的恶性转化。具体目标#2。 ABL1 介导的肿瘤抑制活性的机制。 a) 我们将利用 ABL1 突变体来确定细胞核和/或细胞质 ABL1 是否是肿瘤抑制因子。 b) 我们将查明负责 ABL1 肿瘤抑制活性的上游和下游信号通路。具体目标#3。 ABL1 激酶作为白血病的治疗靶点。 a) 我们将确定 ABL1 变构激活剂 (DPH) 是否也能增强靶向 TKI 的抗白血病功效原代 AML/MPN 细胞中的 FLT3(ITD) 和 JAK2(V617F)。 b) 我们将结合测试新的治疗方法 DPH + 已批准使用携带 BCR-ABL1、FLT3(ITD) 或 JAK2(V617F) 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 ABL1 激酶激活剂。该提议可能会鉴定出新的诊断标志物（ABL1 缺失），从而导致癌症恶性进展。白血病。此外，ABL1 表达后可能成为新型抗白血病方法的有效靶点。