Molecular pathogenesis of myelodysplastic syndrome

Abstract

Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells characterized by ineffective and inadequate hematopoiesis and susceptibility to acute myeloid leukemia (AML). Cytogenetic abnormalities are seen in half of MDS patients, and generally consist of partial or complete chromosome deletion or addition, whereas balanced translocations frequently seen in AML are rare. It seems that gene mutations are more frequently implicated in the pathogenesis of MDS. Two types of gene abnormalities are suspected to be required for developing MDS. The "master" type mutations play a pivotal role in the differentiation block of hematopoietic stem cells, and the "partner (second hit)" type mutations confer a proliferative and/or survival advantage to cells. The mutations of transcriptional factors acting as a critical regulator of hematopoiesis, such as AML1/RUNX1 and C/EBP α, have been reported to be the master mutations. Moreover, the mutations of the genes affecting the RAS-RTK signaling pathway were frequently seen in the MDS/AML patients with AML1 mutations, suggesting that these mutations act as the genetic partners of the AML1 mutation. To clarify the molecular pathogenesis in each MDS/AML patient would provide an important clue for molecular target therapies.