In a recent paper in Nature, the group of John Dick (University Health Network, Toronto) described the identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.
Rene Marke, PhD student at the laboratory of Pediatric Oncology, performed a research internship during his MMD Master program in the Dick group and contributed as co-author to this publication.
Acute myeloid leukaemia (AML) is typically diagnosed without observation of a pre- leukaemic phase. Therefore, it remains difficult to identify the leukaemia initiating cells and both the nature and biological consequences of initiating lesions as well as the order of subsequent mutations remain poorly understood. Single cell DNA analysis of leukaemic samples have allowed the identification of subclones harboring different genetic leasions and have allowed identification of driver mutations. Mutations in genes such as DNMT3a or NPM1 are known as early events in the development of pre-leukaemic cells and hold potential to turn into leukemia once they accumulate more mutations in their DNA. However, the process of accumulation of mutations that allows clonal outgrowth of leukaemic clones, has not been described in detail. With this new report, Dick and colleagues shed some light onto this process.
"Initially screening paired diagnosis/relapse AML patient samples for novel mutations conferring chemotherapy resistance, we made an intriguing discovery", Marke explained. We found that recurrent somatic DNMT3a mutations are common in T cells from AML patients indicating that this mutations occurs very early in the development of AML. When further looking into this, were able to show that DNMT3a mutations precede NPM1 mutations in human AML and are present in stem/progenitor cells at diagnosis and remission. Subsequently, we saw that pre-leukaemic HSCs bearing DNMT3a mutations generated multilineage engraftment and had a competitive advantage in xenograft repopulation assays. From this, we concluded that mutations in DNMT3a arise early in AML evolution leading to a clonally expanded pool of pre-leukaemic HSCs from which AML can evolve. This findings deliver new insights into the first steps of leukaemogenesis and provide a paradigm for therapies which are specifically directed towards the early detection and treatment of pre-leukaemic stem cells. Furthermore, preventive screening for such pre-leukaemic stem cells in healthy adults holds potential to help those patients before the disease arises.
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