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.

急性淋巴细胞白血病（全部）的成年患者中，近三分之一与 t（9; 22）形成BCR-ABL癌基因的染色体易位。 BCR-ABL诱导B细胞急性 直接或直接从慢性髓样中心的急性粘性相或以急性呈粘性相位的淋巴细胞白血病 白血病。与其他类型的B-All相比，BCR-ABL阳性B-ALL的预后较差，而且很大 即使在没有BCR-ABL激酶突变的情况下，对酪氨酸激酶抑制剂（TKI）也不敏感 这种类型的TKI抗性的基本机制在很大程度上是未知的。我们假设这一点 必须有关键的下游途径，B-All需要BCR-ABL激活 开发但不能通过通过TKIS抑制BCR-ABL激酶活性来完全关闭 提出与BCR-诱导的TKI抗性不同的BCR-ABL激酶非依赖性机制 ABL激酶结构域突变。这个新颖的想法得到了我们的初步发现的支持 15-脂氧合酶（ALOX15）被BCR-ABL上调，并且在小鼠中B-All Development必需 ALOX15通过用伊马替尼（TKI）抑制BCR-ABL激酶活性来逆转中调。这些 初步发现将Alox15与B-All细胞中的TKI抗性联系起来，为克服的新策略提供了 TKI耐药性在治疗BCR-Alb阳性B-ALL和策略性的其他白血病中，由致癌性诱导 酪氨酸激酶。我们应该提到，关于Alox15途径如何介导TKI是完全未知的 B-all中的抗性，并且更好地了解该ALOX15介导的TKI抗性机制需要 证明Alox15在BCR-ABL诱导的B-All和深入机理中的基本作用 导致对与ALOX15相关途径的完全了解及其对B-All的贡献的研究 发展。毫无疑问，这些研究将有助于制定新的治疗策略 通过靶向ALOX15途径来克服TKI耐药性在处理BCR-ABL阳性B-all。 具体而言，主要是使用基因基因敲除小鼠和CRISPR-CAS9技术采用遗传方法， 我们将通过揭示Alox15的作用及其相关途径在B-ALL发展中的作用来检验我们的假设 在B-All细胞对TKI的响应中。如果成功，结果将对我们更好的影响产生巨大影响 了解B-all疾病机制，并有助于确定治疗TKI不敏感的新目标 人类B-仍然缺乏有效疗法的所有人。具体目的是：1）研究Alox15的作用 脂质代谢物在促进生长和诱导B-all细胞的TKI耐药性方面； 2）研究 ALOX15调节的主要伴侣基因在BCR-ABL诱导的B淋巴机中转化和电阻 白血病细胞到TKIS； 3）制定一种治疗策略来规避人类的TKI耐药性 b-全部通过抑制ALOX15途径。