Synergistic role of signaling and epigenetics in leukemic transformation

信号传导和表观遗传学在白血病转化中的协同作用

• 批准号: 10737736
• 负责人: Ross L Levine
• 金额: $ 106.2万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-17 至 2030-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737736
• 关键词: Attenuated; Cell Compartmentation; Cells; Clinical; Clonal Evolution; Clonal Expansion; Dependence; Development; Epigenetic Process; Evolution; Genomic approach; Hematopoiesis; Homeostasis; Intercept; Malignant - descriptor; Malignant Neoplasms; Modeling; Mutation; Patients; Pre-Clinical Model; Role; Sampling; Signal Transduction; Somatic Mutation; Therapeutic; Tissues; Work; cancer initiation; cancer therapy; cell type; functional genomics; gene network; in vivo; innovation; insight; leukemic transformation; new therapeutic target; novel; novel therapeutics; prevent; response; therapeutic gene; tool; treatment response; tumor progression

PROJECT ABSTRACT We propose to use single cell studies of clinical isolates to explicate how mutations and differentiation status coordinately regulate cell state, clonal expansion and malignant transformation. We will model sequential activation/inactivation of somatic mutations in defined cell compartments and perform functional studies to uncover critical gene networks and therapeutic dependencies. This will include single cell studies in primary patient samples, use of innovative models which allow for sequential mutational activation/inactivation, and functional genomic approaches to delineate mechanisms of transformation and novel therapeutic dependencies. Moreover, we will delineate crosstalk between different cell types in normal and malignant hematopoiesis and how these interactions impact therapeutic response. These tools will be distributed widely to enable studies of tissue development/homeostasis, cell state changes, transformation, and therapeutic dependencies.

项目摘要 我们建议使用临床分离株的单细胞研究来阐明突变和分化状态如何影响临床分离株的功能。 协调调节细胞状态、克隆扩增和恶性转化。我们将模拟连续的 在确定的细胞区室中激活/失活体细胞突变，并进行功能研究， 揭示关键基因网络和治疗依赖性。这将包括原发性肝癌的单细胞研究。 患者样本，使用允许顺序突变激活/失活的创新模型，以及 功能基因组方法来描绘转化机制和新的治疗依赖性。 此外，我们将描绘正常和恶性造血中不同细胞类型之间的串扰， 这些相互作用如何影响治疗反应。这些工具将广泛分发，以便能够研究 组织发育/稳态、细胞状态变化、转化和治疗依赖性。

项目成果

Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms.

• DOI: 10.1016/j.ccell.2017.11.009
• 发表时间: 2018-01-08
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Kleppe M;Koche R;Zou L;van Galen P;Hill CE;Dong L;De Groote S;Papalexi E;Hanasoge Somasundara AV;Cordner K;Keller M;Farnoud N;Medina J;McGovern E;Reyes J;Roberts J;Witkin M;Rapaport F;Teruya-Feldstein J;Qi J;Rampal R;Bernstein BE;Bradner JE;Levine RL
• 通讯作者: Levine RL

Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in IDH2- and TET2-Mutant Acute Myeloid Leukemia.

• DOI: 10.1158/2159-8290.cd-16-1049
• 发表时间: 2017-05
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Shih AH;Meydan C;Shank K;Garrett-Bakelman FE;Ward PS;Intlekofer AM;Nazir A;Stein EM;Knapp K;Glass J;Travins J;Straley K;Gliser C;Mason CE;Yen K;Thompson CB;Melnick A;Levine RL
• 通讯作者: Levine RL

JAK2S523L, a novel gain-of-function mutation in a critical autoregulatory residue in JAK2V617F- MPNs.

JAK2S523L，JAK2V617F-MPN 中关键自动调节残基的一种新型功能获得性突变。

• DOI: 10.1182/bloodadvances.2019001283
• 发表时间: 2020
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Pastore,Friederike;Krishnan,Aishwarya;Hammarén,HenrikM;Silvennoinen,Olli;Yan,Benedict;Levine,RossL
• 通讯作者: Levine,RossL

Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib.

• DOI: 10.1038/s41591-018-0115-6
• 发表时间: 2018-08
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Quek L;David MD;Kennedy A;Metzner M;Amatangelo M;Shih A;Stoilova B;Quivoron C;Heiblig M;Willekens C;Saada V;Alsafadi S;Vijayabaskar MS;Peniket A;Bernard OA;Agresta S;Yen K;MacBeth K;Stein E;Vassiliou GS;Levine R;De Botton S;Thakurta A;Penard-Lacronique V;Vyas P
• 通讯作者: Vyas P

Single-cell genotypic and phenotypic analysis of measurable residual disease in acute myeloid leukemia.

急性髓系白血病可测量残留疾病的单细胞基因型和表型分析。

• DOI: 10.1126/sciadv.adg0488
• 发表时间: 2023
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Robinson,TroyM;Bowman,RobertL;Persaud,Sonali;Liu,Ying;Neigenfind,Rosemary;Gao,Qi;Zhang,Jingping;Sun,Xiaotian;Miles,LindeA;Cai,ShengF;Sciambi,Adam;Llanso,Aaron;Famulare,Christopher;Goldberg,Aaron;Dogan,Ahmet;Roshal,Mikhai
• 通讯作者: Roshal,Mikhai