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The role of non-genetic variability in Acute Myeloid Leukaemia



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Gupta, Shikha 


Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haematopoietic progenitor cells with a dismal survival. It has a strong reliance on epigenetic and transcriptional factors for disease progression. Accordingly, my lab has previously identified KAT2A, a histone acetyl-transferase, as a requirement for AML maintenance, where chemical inhibition of KAT2A promotes differentiation of AML cell lines (Tzelepis et al., 2016). More recently, using a conditional knockout mouse model for Kat2a our lab showed that it sustains KMT2A/MLLT3 AML stem cells. Kat2a is a classical regulator of transcriptional variability, its loss leading to cell-to-cell heterogeneity in transcription levels, including from genes involved in ribosomal biogenesis and translation (Domingues et al., 2020). No recurrent mutations in the KAT2A gene have been described in AML, and it is unclear if and how it participates in pre-leukaemia-to-AML progression. In this thesis, I studied Kat2a loss in 2 mouse models of AML representing forms of human disease with a prolonged pre-leukaemia phase which typically require additional mutations for leukaemia progression. Specifically, I analysed the biology of RUNX1RUNX1T1(9a) and Idh1R132H-initiated AML in a conditional Kat2aKO background and observed consistent acceleration of leukaemia initiation and progression with perpetuation of transformed Kat2aKO cells in vivo. Single-cell RNA sequencing (scRNA-seq) of early-stage Kat2aWT and Kat2aKO RUNX1-RUNX1T1(9a) pre-leukaemia, suggested an increase in transcriptional variability upon Kat2a loss, which was accompanied by diversification of cell fates towards B-lymphocytes and monocytes. Furthermore, pseudo-temporal ordering of single Kat2aKO cells revealed a highly branched trajectory populated with intermediate stages of transformation, including accumulation of leukaemia progenitors with RUNX1-RUNX1T1 signature. In contrast, Kat2aWT cells displayed a linear haematopoiesis trajectory with minimal branching, and an abrupt transition towards the candidate leukaemia progenitor state. Pathway analysis combined with functional studies indicate a mechanistic contribution of cytoplasmic translation and ribosomal biogenesis-associated genes towards leukaemia progression in both models of pre-leukaemia. Taken together, my work suggests that loss of Kat2a results in accelerated pre-leukaemia transformation accompanied with diversification of cell fate transitions including with increased accessibility to cell states prone to transformation. Furthermore, transformation-prone cells may benefit from low biosynthetic activity to progress to a leukaemic state. I hypothesize that Kat2a loss may function similarly in the context of other malignancies. In the future, this knowledge may aid in the development of early diagnostic tools and suggest bespoke therapeutic interventions.





Pina, Cristina


Acute Myeloid Leukaemia, Pre-leukaemia, Single-cell RNA sequencing, Transcriptional variability, Kat2a


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
Lady Tata Memorial Trust (unknown)