Contributions
Abstract: EP396
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Biology & Translational Research
Background
Acute myeloid leukaemia (AML) is considered a highly heterogeneous disease. Novel therapeutic approaches in AML aim to target the molecular mechanisms thought to drive leukemogenesis, but emergent evidence suggests that intra-leukemic composition may be more diverse than previously appreciated. To improve AML outcome, the representation of leukaemic composition in patient derived xenografts and their potential in precision oncology has to be elucidated.
Aims
Interpreting the intra-leukaemic heterogeneity and hierarchy may be challenging in large patient cohorts. Here, we decipher the temporal disease composition of an AML patient through longitudinal sampling and explore the inherent leukaemogenic potential of the primary samples through establishment of serial patient-derived xenograft (PDX) models.
Methods
Primary and PDX-derived samples were analysed in parallell by high-resolution genetic and phenotypic approaches, including sequencing, immunophenotyping and ex vivo drug sensitivity testing.
Results
Comparison of the genetic composition revealed that all PDX samples bore a closer resemblance to other PDX samples than to the distinct primary samples from which they originated, indicating a pattern of convergent molecular evolution likely resulting from the selective force of the murine environment.
Across the primary and PDX samples, we identified at least six discrete leukaemia-initiating cell populations, of which five were characterised by known recurrent mutations in AML, including mutations in ASXL1, FLT3 and two independent NRAS mutations. These populations correlated with immunophenotypically defined cell subsets displaying distinct drug sensitivity profiles, suggestive of distinct functional properties.
Conclusion
Our results indicate that the genetic and phenotypic development are closely intertwined, and that diversity in the leukaemic gene-environment likely influences disease trajectories.
Keyword(s): AML, Clonal expansion, Clonality, Xenotransplantation
Abstract: EP396
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Biology & Translational Research
Background
Acute myeloid leukaemia (AML) is considered a highly heterogeneous disease. Novel therapeutic approaches in AML aim to target the molecular mechanisms thought to drive leukemogenesis, but emergent evidence suggests that intra-leukemic composition may be more diverse than previously appreciated. To improve AML outcome, the representation of leukaemic composition in patient derived xenografts and their potential in precision oncology has to be elucidated.
Aims
Interpreting the intra-leukaemic heterogeneity and hierarchy may be challenging in large patient cohorts. Here, we decipher the temporal disease composition of an AML patient through longitudinal sampling and explore the inherent leukaemogenic potential of the primary samples through establishment of serial patient-derived xenograft (PDX) models.
Methods
Primary and PDX-derived samples were analysed in parallell by high-resolution genetic and phenotypic approaches, including sequencing, immunophenotyping and ex vivo drug sensitivity testing.
Results
Comparison of the genetic composition revealed that all PDX samples bore a closer resemblance to other PDX samples than to the distinct primary samples from which they originated, indicating a pattern of convergent molecular evolution likely resulting from the selective force of the murine environment.
Across the primary and PDX samples, we identified at least six discrete leukaemia-initiating cell populations, of which five were characterised by known recurrent mutations in AML, including mutations in ASXL1, FLT3 and two independent NRAS mutations. These populations correlated with immunophenotypically defined cell subsets displaying distinct drug sensitivity profiles, suggestive of distinct functional properties.
Conclusion
Our results indicate that the genetic and phenotypic development are closely intertwined, and that diversity in the leukaemic gene-environment likely influences disease trajectories.
Keyword(s): AML, Clonal expansion, Clonality, Xenotransplantation