Spectrum and clinical implications of chromatin structure and epigenetic changes in leukemia and lymphoma

Leukemia and lymphoma emerge when hematopoietic precursor cells stop differentiating and expand in an uncontrolled manner. Treatment of these malignancies has been met with some success, particularly in children and young adults. However, severe side effects, such as developmental disabilities and secondary cancers are well-known late effects of curative chemotherapy in younger patients, while primary drug resistance and relapses are common in older adults. To improve outcomes, more selective drugs that target cancer-specific epigenetic changes at chromatin such as histone modifications or DNA methylation are being developed and tested. This approach has had limited success so far probably owing to the yet not fully understood complexity of epigenetic changes and their consequences in leukemia and lymphoma cells and also due to the pleiotropic nature of histone-modifying enzymes that can have alternative substrates and context-dependent changes of activity and specificity. In addition, it has been recognized that epigenetic modifications induce changes in the three-dimensional structure of chromatin leading to situations where far-range insulator and enhancer elements loop close to promoter areas of certain genes and regulate their expression. In leukemia, a significant degree of heterogeneity and hierarchical structure has been observed, where so called “leukemic stem cells” are at the origin and represent one of the major sources of relapse, since they evade therapy and can reinitiate a leukemia after remission. One of the major questions in the field is how to identify and target these LSCs and more recently whether chromatin structure and accessibility are key elements that distinguished LSCs from other leukemic cells. The goal of this Research Topic is to examine, which role three-dimensional chromatin structure, accessibility, and epigenetic modification - and in particular far-range looping of DNA and altered localization of enhancers and insulators - play in leukemia and lymphoma, and whether an overarching mechanism can be found across the different hematological cancer groups and whether this could be exploited for new therapies.