Mechanisms underlying the heterogeneity of myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are hematopoietic stem cell (HSC) disorders in which recurrent chromosome abnormalities and gene mutations define a clonal hematopoiesis. The MDS-initiating cell is a rare HSC which transmits the genetic abnormalities to its myeloid and lymphoid progeny. The heterogeneity of MDS phenotypes could be linked to the diversity of genetic events involving epigenetic regulators, chromatin modifiers, splicing factors, transcription factors and signaling adaptors, the various combinations and order of mutations in cooperating genes, and the variegation of clonal hematopoietic hierarchy. Usually, epigenetic and splicing gene mutations occur first. A combination of one epigenetic event with a splicing gene alteration is frequent. The HSC compartment is invaded by a dominant and few minor clones organized linearly or with a branched architecture. The dominant clone containing the first initiating mutations produces myeloid and lymphoid lineages in transplanted immune-deficient mice. The mutations confer a selective advantage to myeloid progenitors at the expense of lymphoid progenitors. In the context of differentiation, one mutation may favor the amplification of granulo-monocytic progenitor, which drives the transformation into acute myeloid leukemia. Understanding the hierarchy of mutations provides insights on the mechanism of transformation. Investigation of mutation pattern and distribution along the hematopoietic tree may influence the therapeutic decision for targeted therapy.