From pathogenesis to new therapeutic targets in diffuse large B cell lymphoma

弥漫性大B细胞淋巴瘤从发病机制到新的治疗靶点

• 批准号: 10737214
• 负责人: Riccardo Dalla-Favera
• 金额: $ 98.7万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-12 至 2030-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737214
• 关键词: B-Cell NonHodgkins Lymphoma; B-Lymphocytes; BCL2 gene; BCL6 gene; Binding; CAR T cell therapy; CRISPR correction; CRISPR/Cas technology; CXCR4 gene; Cells; Cellular biology; Classification; Clinical; Code; Disease; Down-Regulation; Enhancers; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Glucocorticoid Receptor; Goals; Impairment; Link; Lymphomagenesis; Mutate; Mutation; NR3C1 gene; Nature; Oncogenes; Oncogenic; PRDM1 gene; Pathogenesis; Pathway interactions; Patients; Phenotype; Proto-Oncogenes; Recurrence; Research; Role; Site; Steroid Receptors; Taxonomy; Transcription Repressor; Untranslated RNA; cell growth; genome sequencing; large cell Diffuse non-Hodgkin' s lymphoma; new therapeutic target; novel; prevent; programs; therapeutic target; tumor heterogeneity

PROJECT SUMMARY Diffuse Large B cell Lymphoma (DLBCL) is incurable in ~30% of patients and, despite recent advances in CAR- T cell therapies, remains a significant clinical challenge. One barrier to rationally targeted new therapies is the remarkable heterogeneity of these tumors, which leaves as many as 20-50% of cases unclassified based on cell-of-origin or more recent genetic-based classifications. This may be due in part to the fact that current taxonomies are limited to the analysis of coding regions, representing only 3% of the genome, while further genetic complexity of pathogenetic relevance may reside in the non-coding regulatory portion of the genome. To this end, we recently investigated whether critical regulatory domains such as enhancers and super-enhancers (SEs) could be the site of functionally relevant mutations in DLBCL. We found that regions corresponding to active SEs are highly and specifically hypermutated in 97% of DLBCL cases, as compared to the same loci when not active as SE. Such aberrant SE hypermutation displays signatures of AID activity and is linked to genes encoding B cell regulators and well-established oncogenes. As evidence of oncogenic relevance, we showed that the hypermutated SEs linked to the BCL6, BCL2, and CXCR4 proto-oncogenes prevent the binding and transcriptional downregulation of the corresponding target gene by transcriptional repressors, including BLIMP1 (BCL6) and the steroid-receptor NR3C1 (BCL2 and CXCR4). Of note, CRISPR/Cas9-mediated correction of the SE hotspot mutation restored target gene regulation and impaired cell growth, indicating a key role for the SE mutation in maintaining the transformed phenotype (Bal et al., Nature 2022). Overall, these findings identify a highly pervasive, pathogenetically relevant, mutational mechanism that is likely to significantly influence the current understanding of the somatic genetic landscape of DLBCL. The overall goal of this research program will be to: i) identify and mechanistically dissect the top recurrently mutated/functionally relevant SEs and associated target genes; ii) understand the role of the glucocorticoid receptor pathway, which appears to be commonly targeted by the SE hypermutation mechanism as well as by direct coding mutations, in normal B cell biology and lymphomagenesis. We anticipate that this new layer of genetic alterations will identify novel mechanisms of dysregulation for known oncogenes, as well as new dysregulated genes and pathways, with implications for precision classification and therapeutic targeting of DLBCL.

项目摘要 弥漫性大B细胞淋巴瘤（DLBCL）在约30％的患者中无法治愈，尽管最近在CAR-中取得了进步 T细胞疗法仍然是一个重大的临床挑战。合理针对新疗法的一个障碍是 这些肿瘤的显着异质性，这些肿瘤的遗留多达20-50％的病例未分类 原始细胞或更近期基于遗传的分类。这可能部分是由于当前 分类法仅限于对编码区域的分析，仅占基因组的3％，而进一步 致病相关性的遗传复杂性可能存在于基因组的非编码调节部分。到 这一结局，我们最近研究了关键的监管域（例如增强剂和超级增强剂）是否 （SES）可能是DLBCL功能相关突变的位点。我们发现区域与 与同一基因座相比 不为SE活跃。这种异常的SE超称显示了辅助活动的特征，并与基因有关 编码B细胞调节剂和良好的癌基因。作为致癌相关性的证据，我们表明 与Bcl6，Bcl2和CXCR4原始核基因相关的超沉积的SES可防止结合和 转录阻遏物（包括Blimp1）对相应靶基因的转录下调 （Bcl6）和类固醇受体NR3C1（BCL2和CXCR4）。值得注意的是，CRISPR/CAS9介导的校正 SE热点突变恢复了靶基因调节和细胞生长受损，表明SE的关键作用 维持转化表型的突变（Bal等，自然2022）。总体而言，这些发现确定了 高度普遍，致病性相关的突变机制，可能会显着影响 当前对DLBCL的体细胞遗传景观的理解。该研究计划的总体目标将 to：i）识别并机械地剖析顶部反复突变/功能相关的SE和相关 靶基因； ii）了解糖皮质激素受体途径的作用，似乎通常是 由SE超数机制以及直接编码突变，正常B细胞​​生物学和 淋巴作用。我们预计，这种新的遗传改变将确定 已知癌基因以及新的失调基因和途径的失调，对 DLBCL的精确分类和治疗靶向。

项目成果

Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome.

• DOI: 10.1084/jem.20131448
• 发表时间: 2013-10-21
• 期刊: The Journal of experimental medicine
• 作者: Fabbri G;Khiabanian H;Holmes AB;Wang J;Messina M;Mullighan CG;Pasqualucci L;Rabadan R;Dalla-Favera R
• 通讯作者: Dalla-Favera R

Genetics of Chronic Lymphocytic Leukemia.

• DOI: 10.1097/ppo.0000000000000538
• 发表时间: 2021-07
• 期刊: Cancer journal
• 影响因子: 2.2
• 作者: F. Bosch;R. Dalla-Favera