Modelling and drug targeting of a myeloid neoplasm with atypical 3q26/𝘔𝘌𝘊𝘖𝘔 rearrangement using patient-specific iPSCs

tructural 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, causing myeloid neoplasms with a dismal prognosis. The most recent World Health Organization classification recognises myeloid neoplasms with 𝘔𝘌𝘊𝘖𝘔 rearrangement as acute myeloid leukaemia (AML) with defining genetic abnormalities. Recently, the increasing use of induced pluripotent stem cell (iPSC) technology has helped elucidate the pathogenic processes of haematological malignancies. However, its utility for investigating enhancer hijacking in myeloid neoplasms remains unclear. In this study, we generated iPSC lines from patients with myelodysplastic syndromes (MDS) harbouring 𝘵(3;8)(q26.2;q24) and differentiated them into haematopoietic 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 the 𝘔𝘌𝘊𝘖𝘔 promoter and 𝘔𝘠𝘊 blood enhancer cluster (BENC). Furthermore, we revealed the apoptotic effects of the bromodomain and extra-terminal motif (BET) inhibitor on iPSC-derived MDS cells by suppressing activated 𝘔𝘌𝘊𝘖𝘔. 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.