Functional and Translational Epigenomics of Acute Lymphoblastic Leukemia

急性淋巴细胞白血病的功能和转化表观基因组学

• 批准号: 10356890
• 负责人: MICHAEL L CLEARY
• 金额: $ 36万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356890
• 关键词: Acute Lymphocytic Leukemia; Address; Adult; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Child; Chromatin; Collection; Credentialing; Dasatinib; Data; Dependence; Disease; Epigenetic Process; Foundations; Genes; Genetic; Genetic Transcription; Genomic approach; Genomics; Individual; Libraries; Methods; Modeling; Molecular; Morbidity - disease rate; Oncogenic; Pathogenesis; Pathologic; Pathway interactions; Patients; Phosphotransferases; Protein Tyrosine Kinase; Proteins; Reader; Regulatory Pathway; Resistance; Resistance development; Role; SYK gene; Signal Pathway; TCF3 gene; Therapeutic; Tyrosine Kinase Inhibitor; ZAP-70 Gene; acute lymphoblastic leukemia cell; effective therapy; epigenome; epigenomics; functional genomics; genome-wide; histone methylation; inhibitor; kinase inhibitor; leukemia; leukemogenesis; long-term sequelae; mortality; neoplastic; novel; pharmacologic; pre-B cell receptor; preclinical efficacy; preclinical study; programs; prospective; resistance mechanism; response; small hairpin RNA; targeted treatment; therapeutic target; transcription factor; transcriptome; treatment response; validation studies; whole genome

Project summary Acute lymphoblastic leukemia (ALL) represents a heterogeneous collection of diseases with diverse genetic origins, and it is increasingly apparent that effective treatments must be customized to the individual molecular features of each patient’s disease. To advance this paradigm, this application focuses on the epigenetic mechanisms of pathogenesis and response to targeted therapy in ALL. Studies focus on a distinctive genetic subtype that expresses E2A- PBX1, a chimeric transcription factor that is the major oncogenic driver in 50% of ALL with selective activation of the pre-B-cell receptor signaling pathway (pre-BCR+) and response to tyrosine kinase inhibition in preclinical studies. Although inhibition of activated signaling pathways is a promising therapeutic strategy in ALL, it is complicated by the development of resistance through a variety of mechanisms. Among these, primary epigenetic alterations are recently observed as important underlying pathologic mechanisms that drive the plasticity of the neoplastic state and therapeutic response. In Aim 1, a high throughput genome-wide “omics” approach will be used to elucidate the chromatin landscape subordinate to E2A-PBX1 in ALL cells, correlate the epigenome with the transcriptome, identify mis-regulated target genes, and define their roles in leukemia pathogenesis. In Aim 2, the kinome identified in preliminary studies to be dependent on E2A-PBX1 and required for ALL will be further characterized and interrogated for pathologic roles and therapeutic potential using genetic and pharmacologic methods. In Aim 3, epigenetic mechanisms of resistance to kinase inhibition identified in extensive preliminary studies using a functional genomics approach based on ultracomplex shRNA library screens will be further characterized to prospectively interrogate targeted therapy response in pre-BCR+ ALL using dasatinib resistance as a model. Identified regulatory factors and compensatory resistance pathways amenable to molecular therapy with specific inhibitors targeting chromatin-associated proteins will be evaluated in combination with kinase inhibitors for synergistic efficacy and resistance amelioration. These studies will further characterize the dependence of ALL cells on specific epigenetic effectors, define their roles in various transcriptional and signaling pathways that contribute to ALL pathogenesis, and credential their prospects as therapeutic targets.

项目摘要 急性淋巴细胞白血病（ALL）是一种异质性疾病， 不同的遗传来源，越来越明显的是，有效的治疗必须是 根据每个病人疾病的分子特征定制。推进这一 范例，这种应用程序的重点是发病机制和反应的表观遗传机制 靶向治疗的方法。研究集中在一个独特的基因亚型，表达E2 A- PBX 1，一种嵌合转录因子，是50% ALL伴发白血病的主要致癌驱动因子 前B细胞受体信号通路（前BCR+）的选择性激活和对 酪氨酸激酶抑制的临床前研究。虽然抑制激活的信号传导 通路是ALL中有前途的治疗策略，但由于 通过各种机制进行抵抗。其中，主要的表观遗传改变包括 最近观察到作为重要的潜在病理机制，驱动可塑性的 肿瘤状态和治疗反应。在目标1中，高通量全基因组“组学” 方法将用于阐明ALL中E2 A-PBX 1的染色质景观 细胞，将表观基因组与转录组相关联，鉴定误调节的靶基因，以及 明确其在白血病发病机制中的作用。在目标2中，初步鉴定的激酶组 将进一步描述依赖于E2 A-PBX 1和ALL所需的研究， 使用遗传学和药理学方法研究其病理作用和治疗潜力 方法.在目标3中，鉴定了对激酶抑制的抗性的表观遗传机制， 使用基于超复杂的功能基因组学方法进行了广泛的初步研究， shRNA文库筛选将进一步表征，以前瞻性地询问靶向治疗 使用达沙替尼耐药作为模型，在pre-BCR+ ALL中的应答。确定的调节因素 和代偿性耐药途径，适用于使用特异性抑制剂的分子治疗 靶向染色质相关蛋白将与激酶抑制剂联合进行评价 用于协同功效和抗性改善。这些研究将进一步表征 ALL细胞对特定表观遗传效应物的依赖性，定义了它们在各种疾病中的作用。 转录和信号传导途径，有助于ALL发病机制，并证明其 作为治疗靶点的前景。

项目成果

SETDB2 Links E2A-PBX1 to Cell-Cycle Dysregulation in Acute Leukemia through CDKN2C Repression.

• DOI: 10.1016/j.celrep.2018.03.124
• 发表时间: 2018-04-24
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Lin CH;Wong SH;Kurzer JH;Schneidawind C;Wei MC;Duque-Afonso J;Jeong J;Feng X;Cleary ML
• 通讯作者: Cleary ML

Genome editing-induced t(4;11) chromosomal translocations model B cell precursor acute lymphoblastic leukemias with KMT2A-AFF1 fusion.

• DOI: 10.1172/jci171030
• 发表时间: 2024-01-02
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Pan, Feng;Sarno, Jolanda;Jeong, Johan;Yang, Xin;Jager, Astraea;Gruber, Tanja A.;Davis, Kara L.;Cleary, Michael L.
• 通讯作者: Cleary, Michael L.

Functional characterization of the PI3K/AKT/MTOR signaling pathway for targeted therapy in B-precursor acute lymphoblastic leukemia.

• DOI: 10.1038/s41417-022-00491-0
• 发表时间: 2022-11
• 期刊: CANCER GENE THERAPY
• 影响因子: 6.4
• 作者: Grueninger, Patricia K.;Uhl, Franziska;Herzog, Heike;Gentile, Gaia;Andrade-Martinez, Marta;Schmidt, Tobias;Han, Kyuho;Morgens, David W.;Bassik, Michael C.;Cleary, Michael L.;Gorka, Oliver;Zeiser, Robert;Gross, Olaf;Duque-Afonso, Jesus
• 通讯作者: Duque-Afonso, Jesus

Age and ligand specificity influence the outcome of pathogen engagement on preleukemic and leukemic B-cell precursor populations.

年龄和配体特异性影响病原体参与的结果对peleukemic和白血病B细胞前体人群。

• DOI: 10.1182/bloodadvances.2023010782
• 发表时间: 2023-11-28
• 期刊: BLOOD ADVANCES
• 影响因子: 7.5
• 作者: Atre, Tanmaya;Farrokhi, Ali;Jo, Sumin;Salitra, Samuel;Duque-Afonso, Jesus;Cleary, Michael L.;Rolf, Nina;Reid, Gregor S. D.
• 通讯作者: Reid, Gregor S. D.