Single cell analysis of clonal architecture in acute myeloid leukaemia

Nicola Potter, Farideh Miraki-Moud, Luca Ermini, Ian Titley, Gowri Vijayaraghavan, Elli Papaemmanuil, Peter Campbell, John Gribben, David Taussig, Mel Greaves*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

53 Citations (Scopus)

Abstract

We used single cell Q-PCR on a micro-fluidic platform (Fluidigm) to analyse clonal, genetic architecture and phylogeny in acute myeloid leukaemia (AML) using selected mutations. Ten cases of NPM1c mutant AML were screened for 111 mutations that are recurrent in AML and cancer. Clonal architectures were relatively simple with one to six sub-clones and were branching in some, but not all, patients. NPM1 mutations were secondary or sub-clonal to other driver mutations (DNM3TA, TET2, WT1 and IDH2) in all cases. In three of the ten cases, single cell analysis of enriched CD34+/CD33 cells revealed a putative pre-leukaemic sub-clone, undetectable in the bulk CD33+ population that had one or more driver mutations but lacked NPM1c. Cells from all cases were transplanted into NSG mice and in most (8/10), more than one sub-clone (#2-5 sub-clones) transplanted. However, the dominant regenerating sub-clone in 9/10 cases was NPM1+ and this sub-clone was either dominant or minor in the diagnostic sample from which it was derived. This study provides further evidence, at the single cell level, for genetic variegation in sub-clones and stem cells in acute leukaemia and demonstrates both a preferential order of mutation accrual and parallel evolution of sub-clones.

Original languageEnglish
Pages (from-to)1113-1123
Number of pages11
JournalLeukemia
Volume33
Issue number5
DOIs
Publication statusPublished - 1 May 2019
Externally publishedYes

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