Genetic lineage tracing in clonal haematopoiesis and myeloproliferative neoplasms

Thesis

Clonal haematopoiesis (CH) is a common age-related condition in which somatic mutations accumulate in haematopoietic stem and progenitor cells (HSPCs), leading to the clonal expansion of mutated cells. This process has been causatively linked with atherosclerotic cardiovascular disease and related complications, while it has also been associated with an increased risk of development of myeloid neoplasms, including myeloproliferative neoplasms (MPNs). This DPhil thesis aimed to investigate the pathogenesis of CH and MPNs utilising genetic lineage tracing. I initially focused on the study of granulocytes (as the most abundant type of myeloid cells) against germline DNA through a twin study in a pair of monozygotic twins who presented with adult-onset CALR mutant MPN. I aimed to investigate the origin of their premalignant clones and their subsequent molecular evolution. Lineage tracing of the MPN clone by whole genome sequencing revealed a common clonal origin of the MPN clone, which occurred in utero followed by twin-to-twin transplacental transmission and subsequent similar disease latency. In the next part of the project, I focused on the study of granulocytes against platelets as a surrogate of the megakaryocyte lineage. The aim of this part of my work was to assess whether platelet-biased CH exists in humans and determine its prevalence in normal individuals and myeloid neoplasms. Targeted detection of JAK2V617F and other mutations commonly involved in CH and MPN revealed the presence of platelet-biased/restricted CH, accounting for a significant proportion of the overall prevalence of CH. In conclusion, this DPhil thesis highlights the importance of genetic lineage tracing in CH and MPNs and provides insight into their molecular pathogenesis. It introduces a novel model of MPN pathogenesis, involving a prolonged disease latency between the acquisition of the premalignant MPN clone and the development of established disease, thus opening the potential for early diagnosis and preventive precision treatment strategies. It also describes for the first time presence of platelet-biased CH with direct clinical implications in the detection of CH and relevance within the wider context of diagnosis and monitoring of haematological disorders.

Authors: Sousos, N

• DOI: 10.5287/ora-kojynxp1w
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: precision medicine; platelet; genetic lineage tracing; PLT-biased clonal haematopoiesis; myeloid neoplam; triple-negative MPN; molecular analysis; clonal haematopoiesis (CH); twin study; pathogenesis; PLT-restricted clonal haematopoiesis; myeloproliferative neoplasm (MPN); megakaryocyte
• Subjects: Precision medicine; Biology; Hematology, Experimental; Genetics; Cancer; Blood; Molecular dynamics; Hematology; Diseases in twins