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酪氨酸激酶的原癌基因突变在骨肉瘤的发病机制中起核心作用 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)或附体扩增(NUP214-ABL1)。 表达致癌形式的ABL1激酶的白血病通常含有编码非突变等位基因 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， 由于它在调节细胞运动、黏附、自噬、对DNA损伤的反应、细胞凋亡和 扩散。我们最近报道了BCR-ABL1-ABL1-/-小鼠骨髓细胞产生高度侵袭性 小鼠慢性髓系白血病-原始细胞期(CML-BP)样疾病与恶性程度较低的CML-慢性期疾病的比较 来自BCR-ABL1-ABL1+/+细胞的CML-CP样病。此外，ABL1的缺失刺激了细胞的增殖和 Bcr-abl1小鼠白血病干细胞急剧扩增，髓系分化受阻，基因毒性受抑 应激诱导细胞凋亡，并促进染色体异常的积累。此外，我们还报告说，在 缺乏ABL1，BCR-ABL1细胞对酪氨酸激酶抑制剂(TKI)的敏感性降低，如 反之，变构刺激ABL1激酶可增强BCR-ABL1-TKI的抗白血病作用。 CML阳性和bcr-abl1阳性的急性淋巴细胞白血病(ALL)。 我们推测，正常的ABL1是白血病的肿瘤抑制因子和治疗靶点，不仅是由 Bcr-abl1，但也与其他癌基因有关。为了检验这些假设，我们提出了三个具体目标。 具体目标#1.鉴定ABL1基因缺失导致白血病的遗传变异。 A)我们将确定ABL1缺失在由染色体易位引起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筛查，以检测遗传异常 促进ABL1-/-造血细胞的恶性转化，但不促进其ABL1+/+造血细胞的恶性转化。 特定目的#2.ABL1介导的肿瘤抑制活性的机制。 A)我们将使用ABL1突变体来确定核质和/或细胞质ABL1是否是肿瘤抑制因子。B)我们 将精确定位负责ABL1肿瘤抑制活性的上游和下游信号通路。 特定目的#3.ABL1激酶作为白血病的治疗靶点。 A)我们将确定ABL1的变构激活剂(DPH)是否也能增强靶向TKI的抗白血病效果 原代AMLS/MPNS细胞中的Flt3(ITD)和JAK2(V617F)。B)我们将测试新的治疗方法 DPH+已经批准使用携带bcr-abl1、flt3(ITD)或JAK2(V617F)的原发白血病异种移植的药物。 C)我们将测试更多有效的ABL1激酶激活剂。 这一建议可能识别新的诊断标记(ABL1缺失)，易于发生恶性进展 白血病。此外，ABL1在表达时可能成为新的抗白血病药物的有效靶点。