This series of research papers explores the influence of various stressors on genotype – phenotype relationships in the context of premalignant and malignant hematologic conditions. Mutations translate into phenotypic changes and exposure to organism-intrinsic or organism-extrinsic stressors may reveal differences in clonal fitness with preferential expansion of clones harboring certain traits, as well as primary or secondary drug resistance. Investigation of the effects of pharmacological and other medical interventions on genotype and phenotype is of particular relevance, as this may have profound clinical consequences and therefore is part of the responsibility and due diligence we owe our patients. Using in-depth genetic and functional analysis of MCL cell lines, mouse models, and patient samples, we comprehensively characterized the genetic background of an important mechanism responsible for primary resistance to the BTK inhibitor ibrutinib in mantle cell lymphoma. Here, activation of the non-canonical NFκB pathway was for the first time described as mechanism of primary resistance to ibrutinib. In another research paper, mutational patterns known to be responsible for chronic active NFκB signaling and potentially predictive of response to targeted BCR/NFκB inhibition were described in DLBCL with respect to anatomical location. Likewise, clonal evolution of primary and secondary myelofibrosis and genetic background of leukemic transformation under the JAK inhibitor ruxolitinib were characterized in long-term serial patient samples using whole exome sequencing, ultra-deep targeted sequencing and single cell analysis. With regard to the premalignant condition of clonal hematopoiesis, we described clinical outcome and genetic evolution under the pressure of myelotoxic therapies and allogeneic hematopoietic stem cell transplantation. Interestingly, mutations in the most frequently mutated gene DNMT3A rarely show clonal expansion and seem to be of minor clinical relevance under the pressure of cytotoxic therapies. In contrast, they are associated with immunological effects in the context of allogeneic transplantation, as we observe an increased cumulative incidence of cGvHD and a reduced cumulative incidence of relapse and progression. The later is most probably due to an enhanced GvL reaction when donor CHIP is present in allogeneic HSCs. In addition, disproportionate clonal expansion can be observed in about have of all donor CHIP cases. Together, these findings indicate mutation and context specific behavior of (pre)malignant hematopoietic cells, underlining the need of individual mutation – stressor and genotype – phenotype investigations to approach the overall goal of individualized precision medicine.
