The RUNX1 Research Program (RRP) and Blood Cancer UK have partnered to support quality research addressing a significant unmet need: preventing the progression from germline RUNX1 deficiency to haematological malignancies in individuals with RUNX1 familial platelet disorder (RUNX1-FPD).

Individuals who carry a germline RUNX1 mutation face a markedly increased lifetime risk of blood cancer, yet only about half will progress to leukaemia, and we cannot currently predict who will progress or when. Understanding the biological processes that unfold in the years and decades before overt malignancy is therefore central to our shared goal of developing rational approaches to early detection, risk stratification, and cancer prevention. All proposed projects should be oriented toward advancing that goal.

This call is offered as a highlighted priority area within Blood Cancer UK's open, competitive grant scheme, jointly funded by RRP and Blood Cancer UK. It combines Blood Cancer UK's established review infrastructure and its deep relationships with the UK blood cancer research community with RRP's focused scientific leadership and its unique access to the RUNX1-FPD patient community.

We are particularly interested in proposals that illuminate how germline RUNX1 deficiency reshapes the earliest stages of haematopoietic evolution, before the onset of overt malignancy. Questions of high priority include, but are not limited to:

• Whether germline RUNX1 deficiency alters the clonal architecture and dynamics of haematopoiesis, for example by producing a reduced or dysfunctional stem cell pool, progressive oligoclonality, replicative stress, or differential ageing across lineages, and whether such changes are present from early life or emerge over time.
• Whether RUNX1 deficiency increases somatic mutation burden or gives rise to distinctive mutational processes, including whether it directly impairs DNA damage response and genome maintenance or whether the changes observed reflect chronic replicative demand.
• How clonal evolution proceeds over time in RUNX1-FPD, and how these processes relate to the transition from a stable premalignant state toward malignancy.
• How the biological features above might inform candidate biomarkers of malignant risk or define windows for early intervention.

While the priority area above reflects our highest current interest, this is an open call, and we welcome strong proposals addressing other important questions in RUNX1-FPD that advance our shared prevention mission. These include the role of inflammation and the immune system in disease progression or whether the mutational processes observed arise secondarily from chronic replicative demand; the determinants of clonal selection in RUNX1-FPD, including which acquired mutations drive, or conversely restrain, the expansion of adaptive clones; functional characterisation of RUNX1 variants; and mechanistic or translational work that advances early detection, risk stratification, or future gene correction strategies.

• High-impact research that is unlikely to be performed without the support of this award.
• Studies using primary human RUNX1-FPD samples, supported by a clear and feasible plan for sample access.
• Rigorous, high-resolution approaches well matched to the biological question, capable of characterising clonal architecture, somatic evolution, or mutational processes in RUNX1-FPD.
• Longitudinal study designs that can capture clonal dynamics over time.
• Collaborations that bring together complementary UK and international expertise.
• Proposals addressing promising, innovative directions not yet funded by other agencies.

Equal consideration will be given to junior and senior investigators.