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Hematopoiesis is the process of forming different blood cell types from “hematopoietic stem cells (HSCs)”. The production of different cell types from HSCs takes place thanks to specific molecular signals. Mutations in the genes involved in this process are responsible for a wide range of diseases, from various deficiencies of one or more cell types (platelets, red blood cells or white blood cells, for example), to hematological malignancies such as leukemia. Since the 90s, the role of the Flt3lg gene has been fairly well defined in mice: it is involved in the hematopoiesis process, notably in the differentiation of HSCs into dendritic cells.
Dendritic cells are the sentinels of the immune system, detecting infectious agents and triggering the immune response. There are several categories of dendritic cells, present in lymphoid organs (thymus, spleen) and in the skin or mucous membranes, such as the lungs or intestine.
Prior to the publication of this article, the essential roles of the FLT3LG gene in humans had not been clearly defined, as patients with a mutation inactivating this gene had never been observed. As part of her thesis project, Mana Momenilandi, under the supervision of Vivien Béziat, group leader in the Human Genetics of Infectious Diseases laboratory at Institut Imagine, described the symptoms of three patients in their thirties, from the same family and with the same FTL3LG gene mutation. These three patients, who have been ill since childhood, suffer from recurrent skin, respiratory and digestive infections that have led to severe growth retardation. Their particularly severe skin infections are caused by human papillomaviruses (HPVs), the pathogens behind skin and genital warts, and cervical and oropharyngeal cancers.
At cellular level, patients have a much lower than normal level of HSCs and a significant reduction in certain blood cell populations. In particular, they have virtually no dendritic cells. In the skin, immune cells are present in normal numbers, except for dermal dendritic cells, probably explaining the severe HPV infections.
The observation of these three patients confirms the crucial role of FTL3LG in human dendritic cell differentiation. Unexpectedly, despite the near-total absence of dendritic cells, FTL3LG deficiency does not prevent adulthood, suggesting the existence of compensatory mechanisms for hematopoiesis and immune response.
The crucial aspect of this work, according to Vivien Béziat, is that it “suggests a major role for skin dendritic cells in controlling HPVs. Despite the existence of an effective vaccine, HPV remains the cause of ~10% of female cancers worldwide. The onset of cancer is the consequence of persistent infection in 10% of women infected with high-risk HPV. Beyond the role of FLT3LG, our work indicates that epithelial dendritic cells represent an excellent therapeutic target to halt this march towards cancer in infected women.”
Reference :
FLT3LG governs the development of partially overlapping hematopoietic lineages in humans and mice
DOI : https://doi.org/10.1016/j.cell.2024.04.009
Corresponding author : vivien.beziat@inserm.fr