Discovery Unveils New Mechanism Driving Complex Karyotype in MDS

Myelodysplastic Syndromes (MDS) refers to a group of clonal hematopoietic disorders characterized by ineffective hematopoiesis and morphological dysplasia. Chromosomal instability is a prominent biological feature of MDS, with over 50% of MDS patients harboring chromosomal abnormalities or a complex karyotype. Despite this observation, the mechanisms underlying mitotic and chromosomal defects in MDS remain elusive.

Recently, the research group led by Prof. TONG Hongyan, Director of the Hematology Department of the First Affiliated Hospital, Zhejiang University School of Medicine (FAHZU), published an article entitled “Ectopic expression of the transcription factor ONECUT3 drives a complex karyotype in myelodysplastic syndromes” in The Journal of Clinical Investigation and the paper was selected for the journal’s cover.

In this work, Prof. TONG’s group initially found a correlation between high ONECUT3 expression and complex karyotype in MDS. ONECUT3- overexpression gave rise to more multinucleated variants, hyperdiploid cells, and aberrant chromosome numbers in both Tp53-WT and Tp53-KO mouse embryonic fibroblast (MEF). Moreover, they increased ONECUT3 expression in primary human CD34+ hematopoietic stem/progenitor cells via a precise safe-harbor targeted knock-in technique through CRRISPR/Cas9. The ONECUT3-OE cells displayed multinucleated variants, dysplasia, and aberrant karyotypes.

Through an integration of genome-wide RNA-seq, chromosome immunoprecipitation (ChIP)-seq and other mechanism studies, the researchers demonstrated that ONECUT3 activates Chromosomal Passenger Complex components INCENP and CDCA8 through direct DNA binding. The overexpression of ONECUT3 leads to dysregulation of Chromosomal Passenger Complex and mitotic defects.

This work unveiled an ectopic expression of transcription factor ONECUT3, associated with complex karyotypes, identifies ONECUT3 directly activated INCENP and CDCA8, leading to the accumulation of the chromosome passenger complex (CPC) components in MDS, and suggested the therapeutic potential of ONECUT3-CPC axis, particularly Aurora B inhibitor, in MDS, and even in other cancers with similar molecular mechanisms.