Modelling the earliest events of t(8;21) acute myeloid leukaemia in human embryonic stem cell-derived definitive haematopoietic progenitor cells

Nafria i Fedi, Monica ORCID: https://orcid.org/0000-0002-5329-7966 (2020). Modelling the earliest events of t(8;21) acute myeloid leukaemia in human embryonic stem cell-derived definitive haematopoietic progenitor cells. University of Birmingham. Ph.D.

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Abstract

The t(8;21) translocation generates the aberrant transcription factor RUNX1-ETO and occurs in approximately 10% of all acute myeloid leukaemias. RUNX1-ETO transcripts can be detected in utero and in cells of patients in remission, but its sole expression is insufficient to cause overt leukaemia. Given that t(8;21) patient cells present additional mutations, the epigenetic reprogramming directly mediated by RUNX1-ETO remains unclear. To address this question, we generated human Embryonic Stem Cell lines carrying an inducible RUNX1-ETO transgene, which we subsequently differentiated into definitive haematopoietic progenitors. We show that induction of RUNX1-ETO in already formed progenitors (i) blocks differentiation at an immature stage, (ii) induces a cell-type specific and reversible cell cycle arrest, (iii) abrogates the RUNX1-mediated gene expression program by interfering with RUNX1 binding, resulting in downregulation of haematopoietic, cell cycle as well as DNA repair genes, (iv) closes down a large part of the chromatin accessibility pattern present in adult haematopoietic multipotent progenitors and (v) alters the differentiation of a defined sub-population of progenitors. Our data are consistent with the idea that RUNX1-ETO establishes a precondition for leukaemic transformation by maintaining a reservoir of quiescent pre-leukaemic multipotent progenitors with susceptibility to expand upon acquisition of additional oncogenic events.

Type of Work:	Thesis (Doctorates > Ph.D.)
Award Type:	Doctorates > Ph.D.
Supervisor(s):	Supervisor(s) Email ORCID Bonifer, Constanze c.bBonifer@bham.ac.uk UNSPECIFIED Elefanty, Andrew andrew.elefanty@mcri.edu.au UNSPECIFIED
Licence:	All rights reserved
College/Faculty:	Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department:	Institute of Cancer and Genomic Sciences
Funders:	Other
Other Funders:	Universitas 21, Cancer Research UK, Children's Cancer Foundation (Australia), Murdoch Children’s Research Institute (Australia); Top-up scholarship, The Henry and Rachael Ackman trust (Department of Paediatrics, The University of Melbourne); Travelling scholarship, International Society for Experimental Haematology; Travelling scholarship
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
URI:	http://etheses.bham.ac.uk/id/eprint/10015

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