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
• 负责人: TOMASZ SKORSKI
• 金额: $ 48.54万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 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/9315519
• 关键词: 9q34; ABL1 gene; Acute Lymphocytic Leukemia; Acute leukemia; Adhesions; Alleles; Apoptosis; Autophagocytosis; Blast Phase; Blood; Bone Marrow Cells; CRISPR screen; Cell Adhesion; Cell Nucleus; Cell Proliferation; Cell Survival; Cells; Chromosomal translocation; Chromosome abnormality; Chromosomes, Human, Pair 9; Chronic; Chronic Myeloid Leukemia; Chronic-Phase Myeloid Leukemia; DNA Damage; DNA Repair; Data; Databases; Disease; Drug usage; FLT3 gene; Genetic; Genetic Transcription; 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; 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; tyrosine kinase ABL1

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酪氨酸激酶的组成激活的致癌突变体在发病机理中起着核心作用 急性和慢性白血病。激活通常是由于染色体易位而发生的（bcr- ABL1，Tel-ABL1等）或偶发放大（NUP214-ABL1）。 表达ABL1激酶的致癌形式的白血病通常包含未突出的等位基因编码 正常的ABL1激酶可能在疾病的发病机理和/或对治疗的响应中起重要作用， 鉴于其在调节细胞运动，粘附，自噬，对DNA损伤的反应，凋亡和凋亡的反应中的重要作用 增殖。我们最近报道BCR-ABL1-ABL1 - / - 鼠骨髓细胞产生了高度侵略性的 慢性粒细胞性白血病阶段（CML-BP）类似小鼠的疾病，而恶性CML-CHRONIC 来自BCR-ABL1-ABL1+/+细胞的相（CML-CP）类似疾病。另外，ABL1的损失刺激了增殖和 BCR-ABL1鼠白血病干细胞的显着膨胀，骨髓分化，抑制了遗传毒性 压力诱导的凋亡，并促进染色体畸变的积累。此外，我们报告了 没有ABL1，BCR-ABL1细胞显示出对酪氨酸激酶抑制剂（TKI）的敏感性降低的 伊马替尼；相反，ABL1激酶的变构刺激TKI在BCR-ABL1-中增强了抗白血病的作用 阳性CML和BCR-ABL1阳性急性淋巴细胞白血病（ALL）。 我们假设正常ABL1是白血病中肿瘤抑制和治疗靶标，不仅是由 bcr-abl1，但也由其他癌基因。为了检验这些假设，我们提出了3个具体目标。 特定目标＃1。从ABL1丧失诱导白血病的遗传像差的鉴定。 a）我们将确定ABL1损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）我们将执行全基因组CRISPR筛查以检测遗传畸变 促进ABL1 - / - 造血细胞的恶性转化，而不是其ABL1+/+对应物。 特定目标＃2。 ABL1介导的肿瘤抑制活性的机制。 a）我们将使用ABL1突变体来确定核和/或细胞质ABL1是否是肿瘤抑制剂。 b）我们 将确定负责ABL1肿瘤抑制活性的上游和下游信号通路。 特定目标＃3。 ABL1激酶作为白血病的治疗靶点。 a）我们将确定ABL1（DPH）的变构激活剂是否还提高了TKIS靶向的抗白血病功效 原代AMLS/MPNS细胞中的FLT3（ITD）和JAK2（V617F）。 b）我们将测试新型的治疗方法结合 DPH +已经使用携带BCR-ABL1，FLT3（ITD）或JAK2（V617F）的原发性白血病异种移植物批准了药物。 c）我们将测试更有效的ABL1激酶激活剂。 该建议可以确定新颖的诊断标记（ABL1丢失）易于恶性进展 白血病。此外，ABL1表示时，可能是新型抗白血病方式的有效目标。