Poster Presentation 16th Asian Conference on Transcription 2019

Dysregulated transcriptional response to differentiation signals in cohesin-mutant leukemia cells (1170)

Jisha Antony 1 2 , Gregory Gimenez 1 , Terry Taylor 2 , Umaima Khatoon 1 , Robert Day 1 , Ian M Morison 1 , Julia A Horsfield 1
  1. The University of Otago, Dunedin, NZ, New Zealand
  2. Southern Community Laboratories, Dunedin, New Zealand

Mutations in the subunits of the cohesin complex, particularly in the STAG2 subunit, have been identified in a range of myeloid malignancies, but it is unclear how these mutations progress leukaemia. Here, we created isogenic K562 erythromyeloid leukaemia cells with and without the known leukemic STAG2 null mutation, R614*. STAG2 null cells acquired stem cell and extracellular matrix gene expression signatures that accompanied an adherent phenotype. Chromatin accessibility was dramatically altered in STAG2 null K562, consistent with gene expression changes. Enhanced chromatin accessibility was observed at genes encoding hematopoietic transcription factors, ERG and RUNX1. Upon stimulation of megakaryocyte differentiation using phorbol 12-myristate 13-acetate (PMA), STAG2 null cells showed a precocious spike in RUNX1 transcription that was associated with enhanced transcription from its proximal P2 promoter. A similar precocious spike was observed in transcription of ERG. Interestingly, unrestrained transcription of these genes was confined to early time points of differentiation. Treatment of STAG2 null cells with enhancer-blocking BET inhibitor, JQ1, dampened precocious RUNX1 P2 expression and blocked of RUNX1 P1 and ERG transcription during PMA stimulation in both parental and STAG2 null cells These results suggest that precocious RUNX1 and ERG transcription in STAG2 null cells is enhancer-driven. Furthermore, JQ1 treatment reduced stem cell-associated KIT expression in STAG2 null mutants. We conclude that STAG2 depletion in leukemic cells amplifies an enhancer-driven transcriptional response to differentiation signals, and that this characteristic is dampened by BET inhibition. The results are relevant for development of therapeutics in cohesin mutant myeloid leukaemia.