Translating genomic discoveries to improved outcomes for high risk acute leukemia

将基因组发现转化为改善高危急性白血病的结果

• 批准号: 10738122
• 负责人: Charles G. Mullighan
• 金额: $ 109.2万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-19 至 2030-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738122
• 关键词: Acute; Acute leukemia; Area; Bar Codes; Cancer Etiology; Cause of Death; Cell Lineage; Cells; Cessation of life; Childhood Leukemia; Chromatin; Clonal Evolution; Collaborations; Development; Disease; Engineering; Enhancers; Event; Experimental Models; Fusion Oncogene Proteins; Gene Expression; Genetic Transcription; Genomics; Glues; Goals; Hematopoietic; LMO2 gene; Liquid substance; Malignant Neoplasms; Mediating; Molecular; Molecular Bank; Pediatric Neoplasm; Phase; Physical condensation; Research; Role; Taxonomy; Therapeutic; Translating; Treatment Failure; adult leukemia; high risk; improved; improved outcome; innovation; insight; leukemia; leukemogenesis; mouse model; multiple omics; novel; novel diagnostics; novel therapeutic intervention; programs; protein degradation; small molecule libraries; targeted treatment; therapeutic development; therapeutic target

ABSTRACT Acute leukemia is a leading cause of death in the young. The goal of my research program is to identify the genomic drivers of leukemogenesis and treatment failure, and through experimental modeling gain mechanistic insight to enable the development of new diagnostic and therapeutic approaches, and ultimately improve cure rates for this disease. In the last project period, I identified multiple subtypes of leukemia that led to a revision of the molecular taxonomy of acute lymphoblastic and lineage ambiguous leukemia; I defined the relationship of genomic variegation and clonal evolution in leukemia; I demonstrated the role of liquid-liquid phase separation in leukemogenesis; and I developed new therapeutic approaches using targeted protein degradation directed at intractable drivers of high-risk leukemia. In this proposal, the original overarching goal remains unchanged, but my research program will address several conceptually new areas of research that have been stimulated by my prior discoveries. These include (1) defining the mechanism by which enhancer deregulation drives leukemogenesis in T-lineage ALL; (2) investigating how concomitant LMO2-activating and STAG2-inactivating alterations perturb chromatin state to drive leukemogenesis, and how this may be exploited for therapeutic benefit; (3) elucidating how BCL11B deregulation primes primitive hematopoietic cells for lineage ambiguous leukemia; (4) determining how fusion oncoprotein-driven liquid-liquid phase separation (LLPS) drives chromatin and transcriptional deregulation in leukemogenesis, and how this may be targeted for therapeutic benefit; and (5) developing molecular glue-based targeted protein degradation strategies to improve cure rates for childhood leukemia. These research areas explore central questions in childhood and adult leukemia, including the mechanisms by which enhancer hijacking/deregulation events drive leukemogenesis, the basis of cell lineage ambiguity in lineage ambiguous leukemia, the mechanistic role of LLPS in leukemogenesis, and the efficacy of innovative therapeutic approaches to degrade intractable drivers of acute leukemia. To achieve these goals I will use innovative experimental approaches including novel engineered mouse models, single cell barcoding and lineage tracing, multiomic gene expression-chromatin profiling, LLPS-condensate profiling, and exploitation of a unique small molecule library of molecular glues. This research program will be facilitated by collaborations with colleagues with expertise in these approaches. Collectively, these approaches will yield fundamental mechanistic insight and therapeutic advances that will improve cures for currently intractable high risk leukemias.

摘要 急性白血病是年轻人死亡的主要原因。我的研究计划的目标是找出 白血病发生和治疗失败的基因组驱动因素，并通过实验建模获得机制 洞察力，使新的诊断和治疗方法的发展，并最终提高治愈 对于这种疾病的价格。在上一个项目期间，我发现了白血病的多种亚型，从而导致了对 急性淋巴细胞白血病和谱系不明白血病的分子分类学;我定义了 白血病中的基因组变异和克隆进化;我证明了液-液相分离的作用 我开发了新的治疗方法，使用靶向蛋白质降解， 高危白血病的顽固驱动因素。在这项提案中，最初的总体目标保持不变，但 我的研究计划将涉及几个概念上的新研究领域，这些领域是由我的 先前的发现这些措施包括（1）定义增强子放松管制驱动的机制 T细胞系ALL的白血病发生;（2）研究伴随LMO 2激活和STAG 2失活 改变扰乱染色质状态以驱动白血病发生，以及如何利用这一点进行治疗 （3）阐明BCL 11B失调如何引发原始造血细胞的谱系模糊 白血病;（4）确定融合癌蛋白驱动的液-液相分离（LLPS）如何驱动染色质 以及白血病发生中的转录失调，以及如何将其作为治疗益处的靶点;以及 (5)开发基于分子胶的靶向蛋白质降解策略，以提高儿童的治愈率 白血病这些研究领域探索儿童和成人白血病的核心问题，包括 增强子劫持/失调事件驱动白血病发生的机制，细胞谱系的基础 谱系不明确白血病的不明确性，LLPS在白血病发生中的机制作用，以及LLPS的疗效。 创新的治疗方法，以降低急性白血病的难治性驱动因素。为了实现这些目标，我将 使用创新的实验方法，包括新的工程小鼠模型，单细胞条形码， 谱系追踪、多组基因表达-染色质分析、LLPS-冷凝物分析以及开发一种 独特的分子胶小分子库。这项研究计划将通过与以下机构的合作来促进： 在这些方法中具有专业知识的同事。总的来说，这些方法将产生基本的机械 洞察力和治疗进展，将提高治愈目前难治性高危白血病。

项目成果

Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines.

• DOI: 10.1038/s41467-024-44698-1
• 发表时间: 2024-01-16
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Nishiguchi, Gisele;Mascibroda, Lauren G.;Young, Sarah M.;Caine, Elizabeth A.;Abdelhamed, Sherif;Kooijman, Jeffrey J.;Miller, Darcie J.;Das, Sourav;McGowan, Kevin;Mayasundari, Anand;Shi, Zhe;Barajas, Juan M.;Hiltenbrand, Ryan;Aggarwal, Anup;Chang, Yunchao;Mishra, Vibhor;Narina, Shilpa;Thomas, Melvin;Loughran, Allister J.;Kalathur, Ravi;Yu, Kaiwen;Zhou, Suiping;Wang, Xusheng;High, Anthony A.;Peng, Junmin;Pruett-Miller, Shondra M.;Daniels, Danette L.;Urh, Marjeta;Shelat, Anang A.;Mullighan, Charles G.;Riching, Kristin M.;Zaman, Guido J. R.;Fischer, Marcus;Klco, Jeffery M.;Rankovic, Zoran
• 通讯作者: Rankovic, Zoran

Single-cell analysis of acute lymphoblastic and lineage-ambiguous leukemia: approaches and molecular insights.

急性淋巴细胞白血病和谱系模糊性白血病的单细胞分析：方法和分子见解。

• DOI: 10.1182/blood.2022016954
• 发表时间: 2023
• 期刊: Blood
• 影响因子: 20.3
• 作者: Iacobucci,Ilaria;Witkowski,MatthewT;Mullighan,CharlesG
• 通讯作者: Mullighan,CharlesG

Pediatric acute lymphoblastic leukemia.

• DOI: 10.3324/haematol.2020.247031
• 发表时间: 2020-11-01
• 期刊: Haematologica
• 影响因子: 10.1
• 作者: Inaba H;Mullighan CG
• 通讯作者: Mullighan CG

CytofIn enables integrated analysis of public mass cytometry datasets using generalized anchors.

• DOI: 10.1038/s41467-022-28484-5
• 发表时间: 2022-02-17
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Lo YC;Keyes TJ;Jager A;Sarno J;Domizi P;Majeti R;Sakamoto KM;Lacayo N;Mullighan CG;Waters J;Sahaf B;Bendall SC;Davis KL
• 通讯作者: Davis KL

G3BP2-KIT drives leukemia amenable to kinase inhibition in Ph-like ALL.

• DOI: 10.1182/bloodadvances.2021004854
• 发表时间: 2022-06-14
• 期刊: BLOOD ADVANCES
• 影响因子: 7.5
• 作者: Iacobucci, Ilaria;Fukano, Reiji;Friske, Jake D.;Qu, Chunxu;Janke, Laura J.;Zhao, Yaqi;Baviskar, Pradyuamna;Backhaus, Emily A.;Chockley, Peter;Seth, Aman;Laird, A. Douglas;Advani, Anjali S.;Mullighan, Charles G.
• 通讯作者: Mullighan, Charles G.