Understanding clonal dynamics in normal and malignant haematopoietic stem cells

Ever since their discovery, haematopoietic stem cells (HSCs) have become the paradigm for understanding somatic stem cell systems. Throughout my doctoral research, I explored questions in HSC clonal dynamics by high-throughout in vitro and in vivo single-cell assays, state-of-the-art computational analysis and powerful mouse models of myeloid malignancies.
In Chapter 3, I dissected clonal evolution, functional and molecular profiles of single HSCs residing within the marrow of different bones. Phylogenetic analysis demonstrated that HSCs stay embedded their seeded location from embryogenesis. At the same time, single-cell molecular and in vivo transplantation analysis revealed that biological HSC properties are largely dictated by the tissue they reside in, thereby challenging some of the classical views on HSC migration and impact of anatomical location.
To continue in Chapter 4, I conveyed the power of somatic mutations to study preleukaemic competition dynamics. Leveraging on HSC ex vivo expansion and split cultures, a novel in vitro model of clonal competition unveiled the TET2-super competitor clones. These were highly efficient at impairing the growth of their wild-type counterparts. These findings imply that supercompetitive behaviour could be one of the fundamental mechanisms driving clone expansion in myeloid cancers.
Given the multifaceted nature of cancer, in chapter 5 I profiled the synergy between JAK2 and TET2 mutations and IP-10, a key inflammatory molecule. By generating an allelic series of MPN mouse models, we found that, albeit mildly, loss of IP-10 rescued the severe red cell phenotype driven by JAK2 V617F, and partially restored erythroid development. The paramount importance of dissecting the role of different inflammatory cytokines is therefore reinforced by this study.
In summary, this doctoral research has shed new light on HSC clonal dynamics, clonal competition and the bone marrow microenvironment in health and disease, hopefully accelerating the burgeoning HSC biology field.