How Recent Advances in High-risk Myelodysplastic Syndrome Physiopathology May Impact Future Treatments

Myelodysplastic Syndromes (MDSs) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis that often develop into acute myeloid leukemia (AML). MDSs are predominant in the elderly with an incidence of 20/100000 at 70 years of age. To date, the only curative treatment is allogeneic stem cell transplantation; however, a majority of patients are not eligible for this therapy. Azacitidine (AZA), a hypomethylating agent, remains the primary treatment for MDS patients, which leads to a significant increase in overall survival (OS), although it is not curative. Although it is well known that the impairment of apoptosis and differentiation are important features of this complex disease, the implication of autophagy in the pathogenesis of MDS is an emerging concept. Another significant advance in MDS pathogenesis research is the recent identification of mutations in genes encoding transcription factors implicated in hematopoiesis and proteins involved in splicing (SF3B1), methylation (DNMT3A), regulation of methylation (TET2 and IDH), DNA conformation (EZH2 and ASXL1) and differentiation (N- and K-RAS). Additionally, BCL2 family member expression and regulation may also affect the physiopathology of this disease. We have recently reported that targeting autophagy may be an interesting option for the treatment of AZA-resistant patients. Thus, targeting the products of the above-mentioned genes or the signaling pathways affected by the corresponding proteins may be of great interest for the development of a new arsenal of molecules to fight MDS. In this review, we discuss the new aspects of MDS physiopathology and how recent advances in MDS pathogenesis research may impact future treatments to improve the outcome of MDS patients.