Tracing the developmental lineage tree of HSPCs
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ. Rather the location of the mutations in the DNA is relevant. Using the mutation patterns in the hematopoietic stem and progenitor cells (HSPCs) the team was able to trace the developmental lineage tree of the cells.
Van Boxtel, together with his team, studied healthy blood stem cells from seven people of different ages. 'Blood stem cells divide about once every 40 weeks,' says Van Boxtel, 'and we saw that eleven mutations occur during one division.' The older the test subject, the more mutations the researchers found because the mutations accumulate over the years. Yet, these people were fit as a fiddle.
Nevertheless, mutations in blood stem cells may also lead to leukemia. 'We thought that people with leukemia would have more mutations than healthy people,' says Van Boxtel, 'but this is not the case.' The HSPCs of patients with acute myeloid leukemia (AML) contain as many mutations as those from healthy people. The researchers published their results in the open access journal Cell Reports.
Developmental lineage tree
The researchers also describe how they were able to trace the developmental lineage tree of hematopoiesis using the mutation pattern of HSPCs. 'If you study the pattern of mutations of a cancer cell, you can figure out which cell it comes from,' explains Van Boxtel. 'We have shown this for HSPCs now, but especially for solid tumors the origin of the cancer cell is very relevant for selecting the most effective treatment strategy.' The technique has a lot of potential according to the authors. The next step for Van Boxtel and his team will be to study the origin of causative mutations in second cancers in survivors of pediatric cancer.
'So far, we assumed that new mutations occur as a result of intensive treatment during childhood and cause second cancers later in life. We can now test whether these mutations are indeed new or already existed and contributed to both incidences of cancer. This is relevant knowledge when making a treatment plan for children with cancer.'