SFB 1243: Genetic and Epigenetic Evolution of Hematopoietic Neoplasms

癌症治疗的主要挑战是肿瘤的进化能力，从而逃避身体和治疗施加的选择压力。这种进化过程是由随机的遗传和表观遗传变化推动的，使肿瘤和它们的数十亿细胞成为一个多样化和移动的目标。因此，任何治疗都需要捕获和处理不同癌症和个体患者肿瘤细胞的分子异质性，以确保持久的成功。特别是在分子靶向癌症治疗的时代，预测可能的逃逸途径并通过合适的药物组合和/或剂量方案有效地阻断它们至关重要。理想情况下，明智的治疗决策是基于对遗传和表观遗传改变以及肿瘤的克隆组成如何决定治疗耐药性的演变以及可以利用哪些特定脆弱性的全面理解。该CRC将临床、分子、计算和进化专业知识紧密结合，使我们能够识别、量化和建模导致造血肿瘤最初出现的分子过程和参数，以及它们向治疗耐药性的演变和微环境的影响。在这个CRC中，我们协调研究髓系和淋巴系肿瘤，重点是骨髓增生异常综合征（MDS）、急性髓系白血病（AML）、滤泡性淋巴瘤（FL）、多发性骨髓瘤（MM）和套细胞淋巴瘤（MCL）。我们研究克隆造血及其潜在的表观遗传机制，骨髓生态位和免疫微环境的作用，（epi）遗传进化的速率和机制，以及对凋亡诱导剂，基于抗体的免疫疗法和蛋白酶体抑制剂的疾病抗性机制。由于没有单一的完美的模型系统，我们采取综合的方法，结合细胞培养系统，异种移植模型和转基因小鼠，所有这些都与患者来源的材料和临床试验数据的分析密切相关。我们相信，这种跨学科的方法将促进对肿瘤进化的基本过程的更好理解，并最终改善治疗和患者的预后。

The major challenge in cancer therapy is the capacity of tumors to evolve and thereby escape selection pressures imposed by the body and by therapies. This evolutionary process is fueled by random genetic and epigenetic changes, making tumors with their billions of cells a diverse and moving target. Any therapy therefore needs to capture and tackle the molecular heterogeneity of tumor cells in different cancers and individual patients to ensure lasting success. Especially in the era of molecularly targeted cancer therapies, anticipating possible escape routes and effectively blocking them by suitable drug combinations and/or dosing regimens is critical. Informed treatment decisions are ideally based on a comprehensive understanding of how genetic and epigenetic alterations and the clonal composition of tumors determine the evolution of therapy resistance and which specific vulnerabilities can be exploited. The close integration of clinical, molecular, computational and evolutionary expertise within this CRC enables us to identify, quantify and model the molecular processes and parameters that lead to the initial emergence of hematopoietic neoplasms, their evolution towards therapy resistance and the influence of the microenvironment. Within this CRC, we coordinately study myeloid and lymphoid neoplasms focusing on myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), follicular lymphoma (FL), multiple myeloma (MM) and mantle cell lymphoma (MCL). We study clonal hematopoiesis and its underlying epigenetic mechanisms, the role of the bone marrow niche and the immune microenvironment, the rate and mechanism of (epi)genetic evolution with and without drug treatment and disease resistance mechanisms to apoptosis inducers, antibody-based immunotherapies and proteasome inhibitors. As there is no single perfect model system, we take an integrated approach combining cell culture systems, xenotransplantation models and genetically modified mice, all closely linked with the analysis of patient-derived material and data from clinical trials. We are convinced that this interdisciplinary approach will promote a better understanding of the basic processes of tumor evolution and ultimately improve therapy and patient outcomes.