Figure 1.

Schematic representation showing possible routes to MDS. Somatic mutations are known to occur in the hematopoietic stem cells (HSCs) during normal DNA replication. The basic premise of the long-standing idea is that a cell that is endowed with an advantageous mutation produces a progeny with increased fitness, which is selected and eventually flourishes. During the early stages of life, bone marrow inflammation is at homeostasis. However, with increasing age, genomic instability, age-related inflammation (Inflammaging) and external environmental cues, these ‘potent’ clones accumulate in the bone marrow, reaching a stage known as clonal hematopoiesis of indeterminate potential (ChIP). Notably, all hematopoiesis is clonally derived; however, malignancy can arise when the hematopoiesis become abnormal or marked by acquisition of additional mutations. Therefore, ChIP can turn to MDS once clinical manifestations of the disease are diagnosed. On the other hand, clonal selection and acquisition of certain mutations (with or without additional external factors) can directly result in switching from healthy stage to MDS. As the bone marrow ages, HSC pool becomes depleted with increasing inflammaging and these cells become skewed towards myeloid lineage. Illustration was created with BioRender.com (accessed on 28 June 2021).