The role of YTHDF1 and YTHDF3 in normal and malignant haematopoiesis

Epitranscriptomics is the field of research that investigates the role of post-transcriptional mRNA modifications and the function of their regulating machinery in a wide range of biological contexts. The best characterised modification is N6-Methyladenosine (m6A), placed by the writer complex METTL3-METTL14, removed by ALKBH5 and FTO and recognised by reader molecules including the YTHDF family of proteins. Within haematopoiesis and leukaemia research, the reader YTHDF2, responsible for the decay of mRNA molecules labelled with m6A, has recently emerged as a promising candidate for the treatment of Acute Myeloid Leukaemia (AML) whose inhibition does not derail haematopoiesis in the short term. However, its application in the clinic is impaired by lack of knowledge about the function of related proteins YTHDF1 and YTHDF3, as well as potential mutual interactions. Here, I show that YTHDF1 and YTHDF3 are dispensable for steady-state haematopoiesis and are not required to maintain haematopoietic stem cell (HSC) reconstitution capacity following primary and secondary transplantation. Moreover, deletion of Ythdf1 prolongs the activation state of HSCs following haematopoietic injury by delaying the resolution of inflammatory states, accelerating their recovery following chemotherapy in a time-limited response. To explain its expression in the system, I uncover a role in long-term control of HSC expansion during ageing or upon multiple stimulation to preserve their differentiation capacity and avoid exhaustion. At the same time, inhibition of YTHDF1 impairs AML maintenance by promoting the differentiation of leukemic stem cells, showing a synergistic effect with YTHDF2 inhibition likely due to the contextual activation of pro-apoptotic signalling pathways downstream of TNFR2. These results highlight the potential benefits of YTHDF1 inhibition for patients undergoing chemotherapy and establish a base for the use of broad spectrum YTHDF family inhibitors for the treatment of AML, while easing concerns regarding their short-term toxicity