Targeting CK2 oncogenic pathway to overcome drug resistance in high-risk leukemia

靶向CK2致癌途径克服高危白血病耐药性

• 批准号: 10160808
• 负责人: Sinisa Dovat
• 金额: $ 35.39万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160808
• 关键词: Affinity; Alleles; Apoptosis; Apoptotic; B-Cell Acute Lymphoblastic Leukemia; B-cell precursor acute lymphoblastic leukemia cell; BCL1 Oncogene; Catalytic Domain; Cell Proliferation; Childhood; Clinical Research; Combined Modality Therapy; DNA Binding; DNA-Binding Proteins; Data; Development; Dihydrofolate Reductase; Disease; Disease model; Doxorubicin; Drug resistance; Exhibits; Folic Acid; Folic Acid Antagonists; Genes; Genetic; Genetic Transcription; Homocysteine S-methyltransferase; Impairment; In Vitro; Mediating; Methotrexate; Molecular; NADPH Dehydrogenase; Oncogenic; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phosphotransferases; Pre-Clinical Model; Prognosis; Publishing; Regulation; Repression; Resistance; Role; TYMS gene; Testing; Therapeutic; Therapeutic Effect; Thymidylate Synthase; Transcription Repressor; Treatment Efficacy; Tumor Suppression; Tumor Suppressor Proteins; base; carbene; casein kinase II; cell growth regulation; cellular transduction; chemotherapy; cytotoxic; cytotoxicity; design; effectiveness testing; folic acid metabolism; high risk; in vivo; in vivo evaluation; inhibitor/antagonist; insight; leukemia; leukemogenesis; novel; novel drug combination; overexpression; patient derived xenograft model; pediatric patients; protein function; targeted treatment; therapy design; treatment strategy

SUMMARY The Ikaros (IKZF1) gene encodes a DNA-binding protein that functions as a tumor suppressor and a transcriptional regulator in leukemia. Deletion of one Ikaros allele results in the development of high-risk B-cell acute lymphoblastic leukemia (B-ALL) that is resistant to chemotherapy and has a poor prognosis. Our recently published data show that CK2 (Casein Kinase II), an oncogenic kinase that is overexpressed in B-ALL, phosphorylates Ikaros, which reduces Ikaros DNA-binding affinity and abolishes its activity as a transcriptional regulator. Based on these findings we designed a novel B-ALL treatment strategy to restore Ikaros function by targeting CK2. The inhibition of CK2 with a specific inhibitor, CX-4945, as a single drug, restored Ikaros ability to regulate transcription in high-risk B-ALL with deletion of one Ikaros allele and showed therapeutic efficacy in a preclinical model of this disease. Our new preliminary data suggest that CK2 impairs the ability of Ikaros to repress transcription of genes essential to the folic acid metabolism pathway: MTHFD1 (methylene- tetrahydrofolate dehydrogenase NADP+ dependent 1), MTR (5-methyltetrahydrofolate-homocysteine methyl- transferase) and TYMS (Thymidylate Synthase), as well as the anti-apoptotic gene, BCL-XL. In leukemia, high expression of the folic acid pathway genes and BCL-XL are associated with increased resistance to methotrexate and doxorubicin treatment, respectively. Treatment with the CK2-specific inhibitor, CX-4945, restored Ikaros-mediated repression of the MTHFD1, MTR, TYMS and BCL-XL genes in primary high-risk B- ALL cells. In vitro treatment of high-risk B-ALL with CX-4945 in combination with methotrexate, or doxorubicin exhibits a strong synergistic cytotoxicity. We hypothesize that overexpression of CK2 in high-risk B-ALL impairs Ikaros ability to transcriptionally repress the folic acid pathway and Bcl-XL genes and that CK2 inhibition will restore Ikaros tumor suppressor activity as a transcriptional repressor of these genes in high-risk B-ALL cells resulting in increased sensitivity to methotrexate and doxorubicin treatment. We will test this hypothesis in vivo, using patient-derived xenografts (PDX) from pediatric patients with high-risk B- ALL in the following specific aims: In Aim 1, we will establish the therapeutic efficacy of combination treatment with the CK2 inhibitor (CX-4945) and the folic acid pathway inhibitor (methotrexate) in a preclinical model of high-risk B-ALL and determine the molecular mechanisms that restore Ikaros ability to repress folic acid pathway genes. In Aim 2, we will evaluate the in vivo efficacy of combination therapy with CX-4945 and doxorubicin and analyze the mechanism that restores Ikaros–mediated repression of BCL-XL in high-risk B-ALL. In Aim 3, we will identify the mechanisms through which high expression of CK2 regulates drug resistance and Ikaros tumor suppressor function in B-ALL. Results of the proposed project would establish the therapeutic efficacy of two novel combination treatments for high-risk B-ALL and provide mechanistic insights into the regulation of tumor suppression in pediatric high-risk B-ALL.

概括 ikaros（ikzf1）基因编码一种DNA结合蛋白，该蛋白充当肿瘤抑制剂和A 白血病的转录调节剂。删除一个Ikaros等位基因会导致高风险B细胞的发展 抗化疗法耐药性且预后较差的急性淋巴细胞白血病（B-ALL）。我们最近 发表的数据表明，CK2（酪蛋白激酶II），一种过表达的致癌激酶， 磷酸化ikaros，它降低了ikaros DNA结合亲和力，并废除了其作为转录的活性 监管机构。根据这些发现，我们设计了一种新型的B-All治疗策略，以通过 针对CK2。用特定抑制剂CX-4945作为一种药物抑制CK2，恢复了Ikaros的能力 通过删除一个Ikaros等位基因，调节高风险B的转录，并显示出治疗效率 该疾病的临床前模型。我们的新初步数据表明，CK2损害了Ikaros的能力 抑制对叶酸代谢途径必不可少的基因的转录：MTHFD1（亚甲基） 四氢叶酸脱氢酶NADP+依赖性1），MTR（5-甲基四氢叶酸双层半胱氨酸甲基 - 转移酶）和TYM（胸苷酸合酶）以及抗凋亡基因BCl-XL。在白血病高 叶酸途径基因和BCl-XL的表达与对 方法二邻二酸和阿霉素治疗。用CK2特异性抑制剂CX-4945处理 恢复的Ikaros介导的MTHFD1，MTR，TYMS和BCL-XL基因的代表性在原发性高危B-中 所有细胞。用CX-4945与方法转移酸盐或阿霉素相结合的高风险B-All的体外处理 表现出强烈的协同细胞毒性。我们假设高危B-ALL中CK2的过表达 损害Ikaros的转录能力反映叶酸途径和Bcl-XL基因，并且CK2 抑制作用将恢复Ikaros肿瘤抑制活性，作为这些基因在 高风险的B型细胞导致对方法二邻苯甲酸和阿霉素治疗的敏感性提高。我们 将使用患有高危B-的儿科患者的患者衍生的Xenographic图形（PDX）在体内检验该假设 在以下具体目标中，所有这些：在AIM 1中，我们将建立组合的治疗效率 用CK2抑制剂（CX-4945）和叶酸途径抑制剂（甲氨蝶呤）治疗 高风险B-all的临床前模型，并确定恢复Ikaros能力的分子机制 抑制叶酸途径基因。在AIM 2中，我们将评估组合疗法的体内效率 使用CX-4945和阿霉素，分析恢复Ikaros介导的表示的机制 高风险B-all中的BCl-XL。在AIM 3中，我们将确定高表达的机制 CK2调节B-all中的耐药性和Ikaros肿瘤抑制剂功能。提议的结果 项目将建立两种新型组合治疗的治疗效率，用于高危B-all和 提供机械洞察，以调节小儿高危B-all中肿瘤抑制。

项目成果

Aberrant ARID5B expression and its association with Ikaros dysfunction in acute lymphoblastic leukemia.

急性淋巴细胞白血病中 ARID5B 异常表达及其与 Ikaros 功能障碍的关系

• DOI: 10.1038/s41389-018-0095-x
• 发表时间: 2018-11-12
• 期刊: Oncogenesis
• 影响因子: 6.2
• 作者: Ge Z;Han Q;Gu Y;Ge Q;Ma J;Sloane J;Gao G;Payne KJ;Szekely L;Song C;Dovat S
• 通讯作者: Dovat S

TSLP as a Potential Therapy in the Treatment of CRLF2 B Cell Acute Lymphoblastic Leukemia.

• DOI: 10.3390/ijms24010474
• 发表时间: 2022-12-28
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Increased Incidence of IKZF1 deletions and IGH-CRLF2 translocations in B-ALL of Hispanic/Latino children-a novel health disparity.

• DOI: 10.1038/s41375-021-01133-4
• 发表时间: 2021-08
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: Raca G;Abdel-Azim H;Yue F;Broach J;Payne JL;Reeves ME;Gowda C;Schramm J;Desai D;Dovat E;Hu T;Berg AS;Bhojwani D;Payne KJ;Dovat S
• 通讯作者: Dovat S