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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

基本信息

批准号：
10415828
负责人：
Shaoguang Li
金额：
$ 47.81万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
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：
2017-12-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10415828
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 knockout gene leukemia lipoxin A4 new therapeutic target novel novel therapeutic intervention receptor resistance mechanism response src-Family Kinases

项目摘要

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 t（9;22）染色体易位，形成BCR-ABL癌基因。BCR-ABL诱导B细胞急性淋巴母细胞白血病（B-ALL）直接或从慢性期髓系进展为急性母细胞期白血病与其他类型的B-ALL相比，BCR-ABL阳性B-ALL预后差，即使在不存在BCR-ABL激酶突变的情况下，对酪氨酸激酶抑制剂（TKI）的敏感性也较低，这种TKI抗性的潜在机制在很大程度上是未知的。我们假设 B-ALL需要BCR-ABL激活的关键下游通路发展，但不能通过TKI抑制BCR-ABL激酶活性而完全关闭，提示BCR-ABL激酶非依赖性机制不同于BCR-ABL诱导的TKI耐药。 ABL激酶结构域突变。我们的初步研究结果支持了这一新颖的想法， 15-脂氧合酶（Alox 15）被BCR-ABL上调，并且是小鼠B-ALL发展所必需的，但这一点在BCR-ABL中并不重要。用伊马替尼（一种TKI）抑制BCR-ABL激酶活性不会逆转Alox 15上调。这些初步发现将Alox 15与B-ALL细胞中的TKI耐药性联系起来，为克服TKI耐药性提供了新的策略。 TKI耐药治疗BCR-ABL阳性B-ALL和其他策略性致癌诱导的白血病酪氨酸激酶我们应该提到，关于Alox 15通路如何介导TKI是完全未知的 B-ALL的耐药性，更好地理解这种Alox 15介导的TKI耐药机制需要证明Alox 15在BCR-ABL诱导的B-ALL中的重要作用，并深入研究其机制。导致全面了解Alox 15相关通路及其对B-ALL的贡献的研究发展毫无疑问，这些研究将有助于开发一种新的治疗策略，通过靶向Alox 15途径克服TKI耐药性治疗BCR-ABL阳性B-ALL。具体来说，主要采取基因敲除小鼠和CRISPR-Cas9技术的遗传方法，我们将通过揭示Alox 15及其相关通路在B-ALL发展中的作用来验证我们的假设以及B-ALL细胞对TKI的反应。如果成功的话，结果将对我们产生巨大的影响，了解B-ALL的疾病机制，并帮助确定治疗TKI不敏感的人类B-ALL仍然缺乏有效的治疗方法。具体目的是：1）研究Alox 15在肿瘤细胞中的作用脂质代谢产物在促进B-ALL细胞生长和诱导TKI耐药中的作用 Alox 15调控BCR-ABL诱导的B淋巴细胞转化中的关键配偶体基因和耐药性白血病细胞对TKI的耐受性;以及3）开发用于规避人类TKI耐受性的治疗策略通过抑制Alox 15途径治疗B-ALL。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia.

DOI：
10.1038/s41375-020-0977-8
发表时间：
2020-10
期刊：
Leukemia
影响因子：
11.4
作者：
Parting O;Langer S;Kuepper MK;Wessling C;Li S;Braunschweig T;Chatain N;Maié T;Costa IG;Crysandt M;Huber M;Brümmendorf TH;Koschmieder S;Schemionek M
通讯作者：
Schemionek M

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