Publication highlights

Researchers at the Crick and the University of York with clinicians from Great Ormond Street and Guy’s and St Thomas’ Hospitals have investigated all the kinase enzymes expressed (the kinome) in children with a disease called Multiple Endocrine Neoplasia Type 2 (MEN2), to identify new therapeutic markers and targets. This autosomal dominant disease leads to several cancers including the development of thyroid cancer and is caused by pathogenic variants in the receptor tyrosine kinase RET. But the development and progression of these tumours are not always predictable, even within families with the same RET pathogenic variant. This study identified MEN2 subtype and RET pathogenic variant-specific alterations in signalling pathways including mTOR, PKA, NF-κB and focal adhesions, each of which were subsequently validated in patient thyroid tissue.

Researchers at the Crick have identified genetic changes in blood stem cells from frequent blood donors that support the production of new, non-cancerous cells. The team at the Crick, in collaboration with scientists from the DKFZ in Heidelberg and the German Red Cross Blood Donation Centre, analysed blood samples taken from over 200 frequent donors - people who had donated blood three times a year over 40 years, more than 120 times in total - and sporadic control donors who had donated blood less than five times in total. Samples from both groups showed a similar level of clonal diversity (of blood cells), but the makeup of the blood cell populations was different. For example, both sample groups contained clones with changes to a gene called DNMT3A, which is known to be mutated in people who develop leukaemia. Interestingly, the changes to this gene observed in frequent donors were not in the areas known to be preleukemic.

Research from the Crick has highlighted the importance of matching donor and recipient sex when transplanting haematopoietic stem cells from humans into mice for research. The researchers assessed engraftment of leukaemia stem cells from 38 patients with AML and umbilical cord blood stem cells from healthy donors. Initially, it looked like leukaemia cells from male patients engrafted better than female patients, but this effect disappeared once the patient and recipient mouse were the same sex. he female AML cells were much more sensitive to recipient sex than male AML cells, as engraftment proved very challenging when using male mice. In general, male AML cells engrafted better in both male and female mice.

Dendritic cells are a family of white blood cells that plays a key role in starting the immune response to infection and cancer, as well as vaccination. However, it has been unclear just how many members of the family there are, especially as they can sometimes appear under different guises. Painstaking reconstruction of dendritic cell family trees by the Reis e Sousa lab now shows that there are three basic types of conventional dendritic cells in mice. They are called cDC1, cDC2A and cDC2B and develop in the bone marrow from “baby” dendritic cells that already have decided to become one or the other type. These cDC1, cDC2A and cDC2B precursor cells then leave the bone marrow to grow up in all tissues of the body, where they then act as lookouts to sound the alarm upon detecting infection or cancer development. Equivalent cells are also found in humans, arguing that this is a conserved feature of the dendritic cell family across species. The research clarifies the complexity of the dendritic cell system, opening the door for future studies to study the exact functions of cDC1s, cDC2As and cDC2Bs in the immune system.

Researchers at the Francis Crick Institute and UCL have identified stem cells in the human thymus for the first time. These cells represent a potential new target to understand immune diseases and cancer and how to boost the immune system. The researchers found that these stem cells, named Polykeratin cells, express a variety of genes allowing them to give rise to many cell types not previously considered to have a common origin. They can develop into epithelial as well as muscle and neuroendocrine cells, highlighting the importance of the thymus in hormonal regulation. The researchers isolated Polykeratin stem cells in a dish and were able to show that thymus stem cells can be extensively expanded. They demonstrated that all the complex cells in the thymus epithelium could be produced from a single stem cell, highlighting a remarkable and yet untapped regenerative potential.

Blood is one of the most highly regenerative tissues, with up to a trillion cells being produced daily in adult human bone marrow. A continuous supply of new blood cells throughout life relies on a rare population of hematopoietic stem cells (HSCs). A study from the Bonnet lab has uncovered a hitherto uncharacterised human HSC population which has high repopulating and self-renewal abilities. The ability to isolate and further characterise these cells opens the way to a better understanding of how human haemopoiesis is regulated in health and disease.