Previously undetected mutations in bone marrow stem cells of young donors can be passed to recipients

Physicians use bone marrow stem cells from a donor, transplanted into a recipient, to treat patients with certain cancers or blood disorders. The donors for these procedures, whose blood or bone marrow is used for the procedures, are typically young, to optimize the quality of the donor stem cells.

Previous studies have found that error-corrected sequencing (ECS) of human blood samples, with a limit of detection of ≥0.0001, that nearly every healthy individual >50 years old harbors rare hematopoietic clones, i.e. genetically distinct subpopulations of blood cells caused by genetic mutations. Clonal hematopoiesis of indeterminate potential, or CHIP, is characterized by the presence of mutant hematopoietic stem cell clones in the bone marrow without overt signs of disease. However, emerging evidence suggests that this condition, which is more common in older patients, may not be as innocuous as previously thought, with recent studies connecting CHIP to a variety of medical problems (Xie et al, 2014). These mutations are below the detection limit of standard high-throughput sequencing used for screening. Screening procedures for bone marrow stem cells used for stem cell transplants are critical because even cancer cells have been transplanted from donor to recipient when standard screening procedures are used at hospitals (Maguire, 2019; Maguire, 2019A).

A new study by Wong et al (2020)has raised the possibility that young donors are also passing along mutations in stem cells that could lead to health problems for recipients. The study found that 44% of younger donors had mutations in the transplanted bone marrow stem cells that could raise the risk of conditions that are sometimes seen in recipients, a higher rate than previously suspected. The scientific team also reported that some of these mutations persisted and proliferated in the recipients’ bone marrow for at least a year.  Specifically, Wong et al (2020) performed ECS on 125 blood and marrow samples from 25 matched unrelated donors and recipients. Clonal mutations, with a median variant allele frequency of 0.00247, were found in 11 donors (44%; median, 36 years old). Of the mutated clones, 84.2% of mutations were predicted to be molecularly pathogenic and 100% engrafted in recipients. That is, in all of the patients who were recipients of the bone marrow stem cells (BMSCs), the BMSCs engrafted into the patient and remain alive. Further, 84% of the live BMSCs in the recipient were found to harbor possible pathogenic mutations.

Many questions remain, for example, are these  mutations present in the donor before the BMSCs are taken from the donor, or do the mutations occur during the BMSC collection process? If the mutations are present in the donor before the procedure begins, are the mutations causing problems in the 44% of donors with the CHIP? Because BMSC transplants can lead to many health issues in the recipients (Maguire, 2019A), understanding these mutations and their pathogenicity in both donor and recipient is important. Because BMSC transplants lead to implantation of the donor cells in a manner that is not consistent with a normal niche, that is, the extracellular matrix (ECM) and microenvironment of the implanted stem cells may be abnormal (Wood et al, 2016; Maguire, 2019A), implanted cells with mutations surviving in an abnormal ECM/microenvironment may lead to reprogramming of the implanted cells to a cancerous state (Bhat and Bissell, 2014). The combination of mutations along with an abnormal ECM/microenviornment is what is critical to the reprogramming, not one or the other alone.

References

Bhat R and Bissell MJ (2014) Of plasticity and specificity: dialectics of the microenvironment and macroenvironment and the organ phenotype. Wiley Interdiscip Rev Dev Biol. 3(2):147-63. doi: 10.1002/wdev.130. Epub 2013 Nov 18.

Maguire G. (2019) Transplanted stem cells survive a long time: do they make you sick? J R Soc Med. 2019 Oct;112(10):412-414.