Role of IKAROS in the Biology and Therapy of High-Risk Precursor B-Cell Leukemia

IKAROS 在高危前体 B 细胞白血病的生物学和治疗中的作用

• 批准号: 8802836
• 负责人: KATIA GEORGOPOULOS
• 金额: $ 55.77万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8802836
• 关键词: ABL1 gene; Address; Adhesions; Adult Precursor B Lymphoblastic Leukemia; Apoptosis; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Biological; Biology; California; Cell Survival; Cells; Chromosomes; Chronic Lymphocytic Leukemia; Clinical Research; Combined Modality Therapy; DNA Binding; Dasatinib; Data; Development; Disease; Disease Progression; Dominant-Negative Mutation; Drug Targeting; Eastern Cooperative Oncology Group; Epigenetic Process; FLT3 gene; Focal Adhesion Kinase 1; Future; Gene Family; General Hospitals; Generations; Genes; Genetic; Genomics; Glucocorticoids; Goals; Growth; Human; Imatinib; Immune; Immunophenotyping; In Vitro; Integrins; Investigation; JAK2 gene; Joints; Knowledge; Leukemic Cell; Lymphoid; Malignant - descriptor; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Mutation; Non-Malignant; PDGFRB gene; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Philadelphia Chromosome; Premalignant; Property; Proteomics; Relapse; Research Personnel; Resistance; Role; Sampling; Scientist; Signal Transduction; Staging; Testing; Therapeutic Studies; Translating; Treatment Efficacy; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; Universities; Xenograft Model; chemotherapeutic agent; chemotherapy; combat; efficacy testing; follow-up; high risk; improved; in vitro testing; in vivo; inhibitor/antagonist; kinase inhibitor; leukemia; leukemic stem cell; leukemogenesis; loss of function; mouse model; mutant; novel; novel strategies; outcome forecast; public health relevance; resistance mechanism; response; retroviral transduction; small molecule; targeted treatment; therapy resistant; transcription factor

DESCRIPTION (provided by applicant): Philadelphia chromosome-positive (Ph+) B-cell acute lymphoblastic leukemia (B-ALL) is a malignancy of precursor B-lymphocytes with a high risk for relapse and poor overall survival for which better therapies are needed. Inactivating mutations in the Ikaros (IKZF1) gene encoding lymphoid transcription factors in ~85% of Ph+ B-ALL suggest its tumor-suppressor role in the pathogenesis of B-ALL. The poor prognosis of Ikaros- mutant B-ALL holds true irrespective of the Ph-chromosome status indicating that Ikaros mutations are directly responsible for resistance to chemotherapy. However, the biological role of Ikaros in the pathogenesis and therapy of B-ALL is not understood and is the focus of our current investigation. In the first Aim, an Ikzf1 conditional mouse model will be used to delineate the rol of Ikaros-inactivating mutations in the pathogenesis and poor response to treatment of B-ALL. Preliminary studies have shown that an aberrant increase in integrin signaling and activation of focal adhesion kinase (FAK) in Ikzf1-deficient B-ALL supports stromal-mediated growth and survival, and causes stromal-dependent resistance to BCR-ABL1 tyrosine kinase inhibitors such as dasatinib. Whether inhibition of FAK in Ikaros-mutant B-ALL interferes with leukemic cell survival and restores sensitivity to BCR-ABL1 inhibitors will be tested. Subsequently, a global approach will be taken to examine the signaling and transcriptional networks regulated by Ikaros during B cell precursor differentiation and determine which of these contribute to the precursor B-cell leukemic phenotype. This should identify additional potential drug targets, both downstream of and parallel to the FAK-mediated survival pathway. Finally, Ikzf1-deficient B- ALL appears to be highly resistant to glucocorticoids (GC), and the mechanism thereof will be investigated with the goal of identifying key nodes in the GC resistance pathway that can be exploited for combination therapy of B-ALL. In the second Aim, the knowledge gained from studies in the mouse models of B-ALL will be translated to human B-ALL. Samples from human patients with Ph+ B-ALL will be screened for IKZF1 mutations and propagated in immunodeficient (NSG) mice to expand the leukemic clone and generate leukemic mice for therapeutic studies. The response of human B-ALL to FAK inhibitors either alone or in combination with BCR- ABL1 inhibitors will be tested in vitro and in vivo. IKZF1-deficient Ph+ or Ph- B-ALL samples will also evaluated for activation of signaling and transcriptional pathways identified in Ikzf1-deficient mouse B-ALL. The strong similarities in the properties of mouse and human Ikaros-deficient B-ALL characterized to date suggest that this approach will identify additional druggable targets that are required for the survival and proliferation of therapy- resistant, high-risk human B-ALL. Together, the studies proposed in this application will provide critical new knowledge about the pathogenesis of Ikaros-mutant B-ALL, and set the stage for clinical studies using FAK in novel combination therapies to combat this disease.

描述（由申请人提供）：费城染色体阳性 (Ph+) B 细胞急性淋巴细胞白血病 (B-ALL) 是一种前体 B 淋巴细胞恶性肿瘤，具有高复发风险和较差的总体生存率，需要更好的治疗。约 85% Ph+ B-ALL 中编码淋巴转录因子的 Ikaros (IKZF1) 基因失活突变表明其在 B-ALL 发病机制中具有抑癌作用。无论 Ph 染色体状态如何，Ikaros 突变 B-ALL 的不良预后都是如此，这表明 Ikaros 突变直接导致化疗耐药。然而，Ikaros 在 B-ALL 发病机制和治疗中的生物学作用尚不清楚，这是我们当前研究的重点。在第一个目标中，将使用 Ikzf1 条件小鼠模型来描述 Ikaros 失活突变在 B-ALL 发病机制和治疗反应不良中的作用。初步研究表明，Ikzf1 缺陷的 B-ALL 中整合素信号传导的异常增加和粘着斑激酶 (FAK) 的激活支持基质介导的生长和存活，并导致基质依赖性对 BCR-ABL1 酪氨酸激酶抑制剂的耐药性，例如达沙替尼。将测试 Ikaros 突变 B-ALL 中 FAK 的抑制是否会干扰白血病细胞的存活并恢复对 BCR-ABL1 抑制剂的敏感性。随后，将采用全局方法来检查 B 细胞前体分化过程中 Ikaros 调节的信号传导和转录网络，并确定其中哪些对前体 B 细胞白血病表型有贡献。这应该能够识别出额外的潜在药物靶标，这些靶标既位于 FAK 介导的生存途径的下游，又与 FAK 介导的生存途径平行。最后，Ikzf1缺陷的B-ALL似乎对糖皮质激素(GC)高度耐药，将对其机制进行研究，目标是确定GC耐药途径中可用于B-ALL联合治疗的关键节点。在第二个目标中，从 B-ALL 小鼠模型研究中获得的知识将转化为人类 B-ALL。来自 Ph+ B-ALL 人类患者的样本将进行 IKZF1 突变筛查，并在免疫缺陷 (NSG) 小鼠中繁殖，以扩大白血病克隆并产生用于治疗研究的白血病小鼠。人类 B-ALL 对单独使用 FAK 抑制剂或与 BCR-ABL1 抑制剂联合使用的 FAK 抑制剂的反应将在体外和体内进行测试。 IKZF1 缺陷型 Ph+ 或 Ph- B-ALL 样品还将评估 Ikzf1 缺陷型小鼠 B-ALL 中确定的信号传导和转录途径的激活情况。迄今为止，小鼠和人类 Ikaros 缺陷 B-ALL 特性的强烈相似性表明，这种方法将识别出治疗耐药、高风险人类 B-ALL 生存和增殖所需的其他药物靶点。总之，本申请中提出的研究将提供有关 Ikaros 突变 B-ALL 发病机制的重要新知识，并为在新型联合疗法中使用 FAK 来对抗这种疾病的临床研究奠定基础。