Chromatin organization in myelodysplastic syndrome

Disordered chromatin organization has emerged as a new aspect of the pathogenesis of myelodysplastic syndrome (MDS). Characterized by lineage dysplasia and a high transformation rate to acute myeloid leukemia (AML), the genetic determinant of MDS is thought to be the main driver of the disease's progression. Among the recurrently mutated pathways, alterations in chromatin organization, such as the cohesin complex, have a profound impact on hematopoietic stem cell (HSC) function and lineage commitment. The cohesin complex is a ring-like structure comprised of structural maintenance of chromosomes (SMC), RAD21, and STAG proteins that involve three-dimensional (3D) genome organization via loop extrusion in mammalian cells. The partial loss of the functional cohesin ring leads to altered chromatin accessibility specific to key hematopoietic transcription factors, which is thought to be the molecular mechanism of cohesin dysfunction. Currently, there are no specific targeting agents for cohesin mutant MDS/AML. Potential therapeutic strategies have been proposed based on the current understanding of cohesin mutant leukemogenesis. Here, we will review the recent advances in investigation and targeting approaches against cohesin mutant MDS/AML.