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Shikha Gupta wins best poster at Quantitative Genomics 2019

last modified Jun 13, 2019 03:28 PM

Congratulations to Shikha Gupta, a PhD student in the Pina group, who won best poster at the Quantitative Genomics 2019 meeting, held on 10 June at the Francis Crick Institute.

Shikha Gupta winning poster

Title- Kat2a loss promotes pre-leukaemia to leukaemia transition with increased transcriptional heterogeneity

Authors- Shikha Gupta 1, Ana Filipa Domingues 2,3, George Giotopoulos 2,3, Oliwia Cyran 1, Ryan J. Asby 2,3, George S. Vassiliou 2,3,4 , Brian J. Huntly 2,3 , Sudhakaran Prabakaran 2, 5, Cristina Pina 1,2

University of Cambridge 1Department of Genetics, 2Department of Haematology and 3WT-MRC Stem Cell Institute, UK; 4Wellcome Trust Sanger Institute, UK; 5IISER-Pune, India.

 

Abstract-

 

Acute myeloid leukaemia (AML) is a heterogeneous disease with a dismal prognosis of <30% 5-year survival, and a strong reliance on epigenetic factors for disease progression. Specifically, we have analysed the role of histone acetyl-transferase KAT2A in AML, and identified alternative roles in pre-leukaemia and AML maintenance. Specifically, we observed a requirement for Kat2a in maintenance of leukaemia-propagating cells in MLL-AF9 model [1] and in cell lines [2]. In contrast, Kat2a absence accelerated transformation in 2 pre-leukaemia models, Idh1R132H and RUNX1-RUNX1T1(9a), with documented early fixation of transformed cells and decreased survival in the latter model.

We have previously shown that KAT2A/Kat2a inhibition enhances transcriptional heterogeneity in mouse ES cells [3], a finding akin to the transcriptional noise regulatory role of Kat2a yeast orthologue, Gcn5. We recapitulated these observations in our Kat2a KO MLL-AF9 leukaemia model [1], and asked if they contributed to pre-leukaemia acceleration.

We sorted progenitor-enriched Kit+ BM cells at early pre-leukaemia cell fixation stages of RUNX1-RUNX1T1(9a) disease, and performed single-cell RNA sequencing using 10X Genomics technology. Again, we observed a global enhancement of transcriptional heterogeneity upon Kat2a loss, as measured by coefficient of variation, with moderate changes to mean expression level.

By combining clustering, multidimensionality reduction and pseudo-temporal ordering techniques, we identified transcriptional programmes specifically associated with Kat2aKO-mediated disease progression. Coincidentally with our previous findings in AML maintenance [1], these programmes associate with ribosomal machinery and mitochondrial electron transport activity, suggesting that changes to leukaemia progression rate depend on broad metabolic categories, including through regulation of heterogeneity of gene expression levels.

Future mechanistic investigation of target contribution to AML evolution can indicate novel disease markers for therapeutics and prognosis.

 

[1] Domingues et al, biorXiv 2018 doi

[2] Tzelepis et al, Cell Rep 2016;

[3] Moris et al, Stem Cells 2018;