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Series GSE161662 Query DataSets for GSE161662
Status Public on Nov 08, 2021
Title Identifying non-genetic determinants of malignant clonal fitness at single cell resolution (NSG vs. BL6 barcode-seq)
Organism Mus musculus
Experiment type Other
Summary All cancers emerge following a period of clonal selection and subsequent clonal expansion. Whilst the evolutionary principles imparted by genetic intra-tumour heterogeneity (ITH) are becoming increasingly clear, little is known about the non-genetic mechanisms that contribute to ITH and malignant clonal fitness. Using SPLINTR, a synthetic expressed barcoding strategy, in three clinically relevant mouse models of acute myeloid leukaemia (AML) we find that malignant clonal dominance is a stable and heritable property that is facilitated by the repression of antigen presentation and the increased expression of Slpi, a leukocyte protease inhibitor that has not previously been characterised in AML. Increased transcriptional heterogeneity is a consistent feature enabling clonal fitness in diverse tissue / immune microenvironments and in the context of clonal competition between genetically distinct clones within a uniform microenvironment. Compared to extramedullary sites, leukaemia initiating capacity is most enriched in malignant cells resident within the bone marrow microenvironment and leukaemia stem cells (LSC), like normal haematopoietic stem cells, display heritable clone-intrinsic properties of high, and low clonal output that contribute to the overall tumour mass. Finally, we demonstrate that clonal output does not dictate sensitivity to chemotherapy and both high and low output LSC clones retain marked cellular plasticity enabling them to survive potent therapeutic challenge and persist as minimal residual disease. Together these data provide fundamental insights into the non-genetic transcriptional processes that underpin malignant clonal fitness which may inform future therapeutic strategies.
 
Overall design DNA barcode-seq of MLL-AF9 leukaemia cells transplanted into Ptprca or NSG mice
 
Contributor(s) Dawson MA, Fennell K, Vassiliadis D
Citation(s) 34880496
Submission date Nov 17, 2020
Last update date Jan 17, 2022
Contact name Mark Dawson
E-mail(s) mark.dawson@petermac.org
Organization name Peter MacCallum Cancer Centre
Street address 305 Grattan Street
City Melbourne
State/province VIC
ZIP/Postal code 3000
Country Australia
 
Platforms (1)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (13)
GSM4912414 Ptprca_mouse1_BM
GSM4912415 Ptprca_mouse1_spleen
GSM4912416 Ptprca_mouse2_BM
This SubSeries is part of SuperSeries:
GSE161676 Identifying non-genetic determinants of malignant clonal fitness at single cell resolution
Relations
BioProject PRJNA679036
SRA SRP292949

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Supplementary file Size Download File type/resource
GSE161662_KF08BarcodeCPM.txt.gz 49.9 Kb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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