Cardiovascular and oncological diseases represent the global major causes of death. For both, a novel and far-reaching risk factor has been identified: clonal hematopoiesis (CH). CH is defined as clonal expansion of peripheral blood cells on the basis of somatic mutations, without overt hematological malignancy. The most commonly affected genes are TET2, DNMT3A, ASXL1 and JAK2. By the age of 70, at least 20–50% of all individuals carry a CH clone, conveying a striking clinical impact by increasing all-cause mortality by 40%. This is due predominantly to a nearly two-fold increase of cardiovascular risk, but also to an elevated risk of malignant transformation. Individuals with CH show not only increased risk for, but also worse outcomes after arteriosclerotic events, such as stroke or myocardial infarction, decompensated heart failure and cardiogenic shock. Elevated cytokine levels, dysfunctional macrophage activity and activation of the inflammasome suggest that a vicious cycle of chronic inflammation and clonal expansion represents the major functional link. Despite the apparently high impact of this entity, awareness, functional understanding and especially clinical implications still require further research. This review provides an overview of the current knowledge of CH and its relation to cardiovascular and hematological diseases. It focuses on the basic functional mechanisms in the interplay between atherosclerosis, inflammation and CH, identifies issues for further research and considers potential clinical implications.

The azanucleosides decitabine and azacytidine are used widely in the treatment of myeloid neoplasia and increasingly in the context of combination therapies. Although they were long regarded as being largely interchangeable in their function as hypomethylating agents, the azanucleosides actually have different mechanisms of action; decitabine interferes primarily with the methylation of DNA and azacytidine with that of RNA. Here, we examine the role of DNA methylation in the lineage commitment of stem cells during normal hematopoiesis and consider how mutations in epigenetic regulators such as DNMT3A and TET2 can lead to clonal expansion and subsequent neoplastic progression. We also consider why the efficacy of azanucleoside treatment is not limited to neoplasias carrying mutations in epigenetic regulators. Finally, we summarise recent data describing a role for azacytidine-sensitive RNA methylation in lineage commitment and in the cellular response to stress. By summarising and interpreting evidence for azanucleoside involvement in a range of cellular processes, our review is intended to illustrate the need to consider multiple modes of action in the design and stratification of future combination therapies.

Myelodysplastic Syndrome (MDS) with del(5q) represents a unique WHO entity, which is often treated with lenalidomide according to standard clinical practice. Guidelines concerning treatment duration have thus far not been implemented, but rather comprise an indefinite therapy until loss of response. This review presents three red blood cell (RBC) transfusion-dependent MDS with del(5q) cases, starting with one rare case with an unbalanced translocation t(2;5), involving the breakpoint of del(5q) and loss of the 5q15-5q31 region. To the best of our knowledge, no comparable case has been described before with a response to lenalidomide. Strikingly, treatment-induced and maintained cytogenetic complete remission (cCR) in this patient. Furthermore, we report two cases of classical del(5q), in which lenalidomide was interrupted after a short period of lenalidomide therapy at the time cCR was achieved. Despite drug holiday cCR was maintained for seven and nine years, respectively. Then del(5q) re-emerged in the absence of novel molecular aberrations and re-treatment with lenalidomide could again achieve cCR in both cases. Together, this series presents three cases of personalized therapy of MDS with del(5q).