Exploring the boundaries of precision haemato-oncology : The case of FLT3 length mutated acute myeloid leukaemia

Abstract

This dissertation explores the astounding biological heterogeneity of acute myeloid leukaemia (AML). In three research papers, we study FLT3 length mutated (LM) AML to contribute to the characterisation of genetic diversity between patients but also within the same patient as the disease develops over time. AML is a rare but severe blood cancer for which outcome is poor. In haemato-oncology as in other cancer fields, the imaginary of precision medicine is a potent force that provides direction to research as well as the development of clinical practice. Specifically, the hope is to tailor cancer management by molecular profiling and therapeutic targeting of actionable aberrations. In the case of AML, the validity and utility of this approach is an open empirical question. The aim of this dissertation is to explore the biological boundaries of precision oncology in the context of AML. I have pursued this aim through empirical characterisation of AML as a heterogeneous and dynamic phenomenon (in the research papers) and a literature study and theoretical reflection on the relationship between that empirical characterisation and available conceptual frameworks of cancer (in the synthesis part of the dissertation). Somatic mutation theory, tumour evolution theory and cancer stem cell theory were identified as the prevailing conceptual frameworks representing variants of explanatory models in AML. These theories also provide justification for the clinical approaches related to precision haemato-oncology. The synthesis provides an overview of empirical FLT3-LM AML research poorly accounted for by these prevailing models, including intra-leukaemic plurality of FLT3-LMs as well as clinico-pathological relationships that suggest context-dependency with regards to FLT3-LM properties. Indeed, in Paper I we confirm the finding that AML patients may have several FLT3-LMs. In Paper II, we show hitherto undiscovered sex differences in genetic profiles of FLT3-LM AML. In Paper III, a single patient is followed through the course of his disease to reveal how genetically diverse cell populations may initiate leukaemia in animal models. These findings pose challenges to the understanding of FLT3-LMs as causal contributors in AML pathogenesis. A major conclusion of this dissertation is that somatic mutation theory is not a sufficient conceptual framework for AML. Evolutionary perspectives seem called for, and the dissertation proposes that a selection-centric perspective to further the understanding and interpretation of FLT3- LM AML pathogenesis, conceptualising both cancer cells and cancer as dynamic phenomena rather than confined entities. Based on this I propose a shift towards characterisation of permissive conditions facilitating the emergence and persistence of disease.