Developing a novel therapeutic strategy for overcoming TKI resistance in ALL

开发一种新的治疗策略来克服 ALL 的 TKI 耐药性

• 批准号: 10057364
• 负责人: Shaoguang Li
• 金额: $ 48.78万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057364
• 关键词: ALOX15 gene; Acute; Acute Lymphocytic Leukemia; Acute leukemia; Adult; Affect; Apoptosis; Arachidonate 15-Lipoxygenase; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; B-cell precursor acute lymphoblastic leukemia cell; Bcr-Abl tyrosine kinase; Binding; Biochemical; CRISPR/Cas technology; Chemicals; Chromosomal translocation; Chronic-Phase Myeloid Leukemia; Data; Development; Disease; Drug resistance; FPR2 gene; Fc Receptor; Foundations; Genes; Genetic; Growth; Hematologic Neoplasms; Human; Hydroxyeicosatetraenoic Acids; Imatinib; Immunocompromised Host; In Vitro; Knockout Mice; Lead; Leukemic Cell; Link; Lipids; Lymphoid; Mediating; Membrane Microdomains; Metabolic; Mus; Mutation; Oncogenic; P-Selectin; PPAR delta; Pathogenesis; Pathway interactions; Patients; Phase; Phosphotransferases; Plasma Enhancement; Play; Prognosis; Protein Tyrosine Kinase; Receptor Gene; Receptor Signaling; Resistance; Role; Signal Transduction; Solid; Testing; Therapeutic; Tyrosine Kinase Inhibitor; Uncertainty; Up-Regulation; abl Oncogene; base; bcr-abl Fusion Proteins; chemotherapy; effective therapy; genetic approach; inhibitor/antagonist; knockout gene; leukemia; lipoxin A4; new therapeutic target; novel; novel therapeutic intervention; receptor; resistance mechanism; response; src-Family Kinases

Nearly one-third of adult patients with acute lymphoblastic leukemia (ALL) are associated with the t(9;22) chromosomal translocation that forms the BCR-ABL oncogene. BCR-ABL induces B-cell acute lymphoblastic leukemia (B-ALL) directly or in acute blastic phase advanced from chronic phase myeloid leukemia. Compared to other types of B-ALL, BCR-ABL-positive B-ALL has a poor prognosis and is much less sensitive to tyrosine kinase inhibitors (TKIs) even in the absence of BCR-ABL kinase mutations, and the underlying mechanisms for this type of the TKI-resistance are largely unknown. We hypothesize that there must be critical downstream pathways whose activation by BCR-ABL is required for B-ALL development but cannot be completely shut down through inhibition of BCR-ABL kinase activity by TKIs, suggesting a BCR-ABL kinase-independent mechanism different from the TKI resistance induced by BCR- ABL kinase domain mutations. This novel idea is supported by our preliminary findings that arachidonate 15-lipoxygenase (Alox15) is upregulated by BCR-ABL and required for B-ALL development in mice but this Alox15 upregulation is not reversed by inhibiting BCR-ABL kinase activity with imatinib (a TKI). These preliminary findings link Alox15 to TKI resistance in B-ALL cells, providing a new strategy for overcoming TKI resistance in treating BCR-ABL-positive B-ALL and strategically other leukemias induced by oncogenic tyrosine kinases. We should mention that it is totally unknown about how the Alox15 pathway mediates TKI resistance in B-ALL, and a better understanding of this Alox15-mediated TKI resistant mechanism requires demonstration of an essential role of Alox15 in B-ALL induced by BCR-ABL and in-depth mechanistic studies that lead to a full understanding of Alox15-associated pathways and their contributions to B-ALL development. Without any doubt, these studies will help to develop a new therapeutic strategy for overcoming TKI resistance in treating BCR-ABL-positive B-ALL by targeting the Alox15 pathway. Specifically, by mainly taking a genetic approach using gene knockout mice and CRISPR-Cas9 technology, we will test our hypothesis by revealing the roles of Alox15 and its related pathways in B-ALL development and in the response of B-ALL cells to TKIs. If successful, the results will have a huge impact on our better understanding of disease mechanisms for B-ALL and help to identify novel targets in treating TKI-insensitive human B-ALL that still lacks effective therapies. The specific aims are: 1) To investigate the role of Alox15 lipid metabolites in promoting growth and inducing TKI resistance of B-ALL cells; 2) To study the roles of Alox15-regulated key partner genes in BCR-ABL-induced B-lymphoid transformation and resistance of leukemia cells to TKIs; and 3) To develop a therapeutic strategy for circumventing TKI resistance in human B-ALL by inhibiting the Alox15 pathway.

近三分之一的成人急性淋巴细胞白血病(ALL)患者与 形成bcr-abl癌基因的T(9；22)染色体易位。Bcr-abl诱导B细胞急性 急性淋巴细胞性白血病(B-ALL)由慢性期发展为急性髓系白血病 白血病。与其他类型的B-ALL相比，BCR-ABL阳性的B-ALL预后较差，且 即使在没有bcr-abl激酶突变的情况下，对酪氨酸激酶抑制剂(TKIs)也不那么敏感，以及 这种类型的TKI耐药的潜在机制在很大程度上是未知的。我们假设 对于B-ALL，必须有关键的下游通路，其被BCR-ABL激活是必需的 但不能通过抑制TKI的BCR-ABL激酶活性而完全关闭， 提示一种不同于BCR-ABL诱导的TKI抵抗的BCR-ABL激酶非依赖性机制。 ABL激酶结构域突变。这一新的想法得到了我们的初步发现的支持，即花生四烯酸 15-脂氧合酶(ALOX15)是由bcr-abl上调的，是B-ALL小鼠发育所必需的，但这 用伊马替尼(一种TKI)抑制BCR-ABL激酶活性并不能逆转ALOX15的上调。这些 初步发现ALOX15与B-ALL细胞中的TKI耐药有关，这为克服 TKI耐药治疗bcr-abl阳性B-ALL和致癌诱导的策略性其他白血病 酪氨酸激酶。值得一提的是，Alox15通路是如何介导TKI的，我们完全不知道 B-ALL中的耐药性，以及对ALOX15介导的TKI耐药机制的更好理解需要 Alox15在bcr-abl诱导的B-ALL中的重要作用及其深入机制的研究 全面了解ALOX15相关通路及其对B-ALL的作用的研究 发展。毫无疑问，这些研究将有助于开发一种新的治疗策略 靶向Alox15途径治疗bcr-abl阳性B-ALL时克服TKI耐药性 具体地说，通过主要采用基因敲除小鼠和CRISPR-Cas9技术的遗传方法， 我们将通过揭示Alox15及其相关途径在B-ALL发育中的作用来检验我们的假设 B-ALL细胞对TKI的反应。如果成功，结果将对我们更好地 了解B-ALL的发病机制并帮助确定治疗TKI不敏感的新靶点 人类B-所有这些仍然缺乏有效的治疗方法。具体目的是：1)研究ALOX15的作用 脂代谢产物在促进B-ALL细胞生长和诱导TKI抵抗中的作用 Alox15在BCR-ABL诱导的B淋巴细胞转化中调节的关键伙伴基因及其耐药性 白血病细胞对TKI的耐药性；以及3)开发一种规避人类TKI耐药性的治疗策略 B-ALL通过抑制Alox15途径。