First name
Thalia
Last name
Vlachou
Year of Study
Research Center
Thesis Title
Functional and genetic heterogeneity in acute myeloid leukaemia
Thesis Abstract
Acute myeloid leukaemia (AML) is the most frequent leukaemia in adults, and still
represents a disease with an unmet medical need, with 50-60% of patients relapsing within
3 years after diagnosis. AMLs are characterised by a high degree of intra-tumour
heterogeneity, both at the biological and the genetic level, which is critical for tumour
maintenance and response to treatments. Biologically, AMLs are organised hierarchically,
with rare stem-like cells (leukaemia stem cells, LSCs) endowed with the unique properties
of self-renewal and differentiation. Genetically, AMLs harbour patient-specific
combinations of different driver mutations, which are organised within individual cases in
sub-clones with distinct growth properties. We hypothesized that tumour maintenance and
relapse in AMLs are driven by the selective expansion of quiescent sub-clones within the
LSC population, which serve as the genomic and functional reservoir of the tumour. The
experimental strategy we employed to test this hypothesis is based on the
xenotransplantation of human leukaemias, the implementation of an in vivo clonal tracking
approach, the functional isolation of leukaemic subpopulations with diverse proliferation
histories and whole-exome sequencing (WES) of bulk and isolated leukaemic
subpopulations. Our aims were to assess the proliferative hierarchy of LSCs and to
examine their intrinsic genetic heterogeneity. We identified two functional LSC classes,
quiescent and cycling, that are in equilibrium in the tumour and largely share the same
clonal architecture. We further observed that genetic leukaemic clones appear to consist of
a high number of individual LSCs, the majority of which exhaust upon serial
transplantation. Finally, by genetic analyses of isolated leukaemic subsets, we were able to
detect a specific enrichment for rare mutations in the quiescent compartment of two patient
xenografts. Our data indicate that tumour evolution is sustained by the quiescent LSC pool
and suggest that their highly proliferating counterpart has a finite lifespan. We expect that
14
the results of our studies will provide new insights into the mechanisms of disease
progression and treatment response in AML, and potentially reveal novel therapeutic
approaches.
represents a disease with an unmet medical need, with 50-60% of patients relapsing within
3 years after diagnosis. AMLs are characterised by a high degree of intra-tumour
heterogeneity, both at the biological and the genetic level, which is critical for tumour
maintenance and response to treatments. Biologically, AMLs are organised hierarchically,
with rare stem-like cells (leukaemia stem cells, LSCs) endowed with the unique properties
of self-renewal and differentiation. Genetically, AMLs harbour patient-specific
combinations of different driver mutations, which are organised within individual cases in
sub-clones with distinct growth properties. We hypothesized that tumour maintenance and
relapse in AMLs are driven by the selective expansion of quiescent sub-clones within the
LSC population, which serve as the genomic and functional reservoir of the tumour. The
experimental strategy we employed to test this hypothesis is based on the
xenotransplantation of human leukaemias, the implementation of an in vivo clonal tracking
approach, the functional isolation of leukaemic subpopulations with diverse proliferation
histories and whole-exome sequencing (WES) of bulk and isolated leukaemic
subpopulations. Our aims were to assess the proliferative hierarchy of LSCs and to
examine their intrinsic genetic heterogeneity. We identified two functional LSC classes,
quiescent and cycling, that are in equilibrium in the tumour and largely share the same
clonal architecture. We further observed that genetic leukaemic clones appear to consist of
a high number of individual LSCs, the majority of which exhaust upon serial
transplantation. Finally, by genetic analyses of isolated leukaemic subsets, we were able to
detect a specific enrichment for rare mutations in the quiescent compartment of two patient
xenografts. Our data indicate that tumour evolution is sustained by the quiescent LSC pool
and suggest that their highly proliferating counterpart has a finite lifespan. We expect that
14
the results of our studies will provide new insights into the mechanisms of disease
progression and treatment response in AML, and potentially reveal novel therapeutic
approaches.
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