Quick summary
An important and complex research study has just been released by a team of Australian researchers at QIMR Berghofer. The study is titled, Single cell long read genotyping of transcripts reveals discrete mechanisms of clonal evolution in post-MPN AML and is available to read in full. The researchers have identified a powerful new way to examine how MPN cells change over time and how some transform into acute myeloid leukaemia.
———————
Overview of article
A small percentage of MPN patients will unfortunately develop acute myeloid leukaemia (AML). This occurs due to extra mutations accumulating in blood stem cells leading to these faulty cells to expand. Until now it’s been difficult to identify which mutations are in which cells and how those mutated cells behave.
This study introduced a powerful new technology that finally enables researchers to identify this. This new single-cell technology maps exactly how mutated blood stem cells behave in MPN and post-MPN AML, revealing multiple distinct evolutionary pathways that lead to leukaemia.
The method the research team created is called LOTR-Seq. It can read long stretches of RNA from individual blood stem cells. It can assess 30 genes for mutations at once and identify which mutations a single cell carries, and that cell’s gene activity and behaviour.
The researchers discovered that in chronic-phase MPN, cells with the JAK2V617F mutation showed clear, distinct patterns of gene activity specific to the MPN subtype. Developing AML from an MPN is generally associated with an additional 2 or more genetic mutations, strongly supporting the hypothesis that the acquisition of these additional mutations drives leukemic transformation. In this study post-MPN AML, researchers assessed nine different mutated sites across six important genes, including JAK2, IDH1 / IDH2, TP53, SRSF2 and U2AF1.
Each mutation was linked to a specific “personality” or behaviour in the cancer cells. The conclusion is that, post-MPN AML isn’t one disease, but a collection of different evolutionary paths depending on which extra mutations the cells pick up.
This research gives the clearest picture yet of how MPNs evolve into AML at the individual cell level. It shows how different mutations drive different routes to leukaemia, which may explain why patients vary so much in how their disease behaves.
Encouragingly, this new LOTR-Seq approach could help identify high-risk patients earlier, by spotting dangerous mutation patterns before AML develops. It may also be able to guide more personalised treatment, because different mutation combinations create different vulnerabilities.
As mentioned, the full article, Single cell long read genotyping of transcripts reveals discrete mechanisms of clonal evolution in post-MPN AML, is free to access if you click on the PDF at that link.
