Modeling and drug targeting of a myeloid neoplasm with atypical 3q26/MECOM rearrangement using patient-specific iPSCs [RNA-seq]
Structural variations involving enhancer hijacking induce aberrant oncogene expression and cause tumorigenesis. A rare translocation, t(3;8)(q26.2;q24), is associated with MECOM and MYC rearrangement, resulting in dismal prognosis. The most recent World Health Organization classification recognizes myeloid neoplasms with MECOM rearrangement as acute myeloid leukemia (AML) with defining genetic abnormalities. To date, patient-derived induced pluripotent stem cell (iPSC) models have helped elucidate the pathogenic processes of human diseases and serve as a valuable platform for drug discovery. However, their utility in cancer biology remains unclear. In this study, we generated iPSC lines from patients with myelodysplastic syndromes (MDS) harboring t(3;8)(q26.2;q24) and differentiated them into hematopoietic progenitor cells to model the pathophysiology of MDS with t(3;8)(q26.2;q24). Our iPSC model reproduced the primary patient's MECOM expression changes and histone H3 lysine 27 acetylation (H3K27ac) patterns in MECOM promoter/enhancer and MYC blood enhancer cluster (BENC). Notably, MDS-iPSCs exhibited H3K27ac activation at the MECOM promoter, even in the pluripotent state, with higher MECOM expression than control iPSCs, indicating that the aberrant histone acetylation of MDS cells could not be completely reset after reprogramming. Furthermore, we revealed the apoptotic effects of the bromodomain and extra-terminal motif (BET) inhibitor JQ1 on iPSC-derived MDS cells by suppressing activated MECOM, suggesting BET inhibitors as potential novel therapeutic drugs for MDS/AML carrying t(3;8)(q26.2;q24). Our study demonstrates the usefulness of iPSC models for uncovering the precise mechanism of enhancer hijacking due to chromosomal structural changes and discovering potential therapeutic drug candidates for cancer treatment. Overall design: We generated iPSC lines derived from MDS clones and iPSC lines derived from normal T cells of a patient with t(3;8)(q26.2;q24). Two groups were compared: Isogenic normal iPSC-derived HPCs (n=3) and MDS-iPSC-derived HPCs (n=3).