Final Report Summary - LEUKEMIABARRIER (The Leukemia-Initiating Cell: Genetic Determinants, Escape Mechanisms and Ontogenic Influence)
The overall goal set out for the project was to understand why normal hematopoietic (blood) cells progress into acute myeloid leukemia (AML).
We started the work by characterising a novel mouse model of MLL-ENL driven AML. This revealed that multiple progenitor cells types can act as leukemia-initiating cells. However, leukemia-competence is lost as defined stages of differentiation, while highly surprising, the most primitive hematopoietic stem cells cannot initiate MLL-ENL driven AML, as this fusion product acts as a tumor-suppressor in these cells. More defined mechanistic pathways included studies on the influence of ribosome biogenesis and hypoxia; two pathways that has convincingly been demonstrated to influence on many types of cancers. We could find little evidence that interference with these pathways would be of benefit to MLL-fusion mediated AML. We evaluated the influence of secondary mutations on AML progression using the MLL-ENL model. This work revealed that, similar to human leukemia with MLL rearrangements, few secondary driver mutations could be identified. When present, secondary mutations converge on the RAS/MAPK; which is well-established also for human MLL-rearranged AML. We were able to demonstrate that the order of mutations has an influence of disease progression, such that when an activating RAS mutation precedes MLL-ENL onset, this affects both latency and different subtypes of leukemia developing.
We explored the well-established concept of cancer cel restriction by host immunity. Again, these concepts have almost exclusively been confined to models of solid cancer. When evaluated in an MLL-ENL AML setting, we could find little evidence that host immunity is a significant barrier to AML development. However, we could clearly observe a role for host immunity upon establishment of leukemia, arguing for the the use of (refined) immunotherapies in MLL-fusion associated AML.
Finally, we have taken dual approach to study both normal and malignant hematopoiesis. A first central question related to the general concept of hematopoietic stem cell ageing. Given the findings from Aim 1 that mutation order might be central for disease progression of AML, we hypothesised that chronological ageing might be underwritten by defined mutations (as has also been suggested in recent work on aged human hematopoiesis). Within the project, we developed an experimental strategy allowing us to convert functionally aged stem cells into iPS cells, followed by the generation of chimeric mice via blastocysts complementations. Counter to our hypothesis, this has revealed aged somatic donor hematopoietic stem cells could be reverted into stem cells with young functional and molecular properties. In more direct work on the influence of ageing on MLL-ENL development, we have recently established that the general poor regenerative properties of ageing hematopoiesis also translates into a poor competence for leukemia-initiation.
We started the work by characterising a novel mouse model of MLL-ENL driven AML. This revealed that multiple progenitor cells types can act as leukemia-initiating cells. However, leukemia-competence is lost as defined stages of differentiation, while highly surprising, the most primitive hematopoietic stem cells cannot initiate MLL-ENL driven AML, as this fusion product acts as a tumor-suppressor in these cells. More defined mechanistic pathways included studies on the influence of ribosome biogenesis and hypoxia; two pathways that has convincingly been demonstrated to influence on many types of cancers. We could find little evidence that interference with these pathways would be of benefit to MLL-fusion mediated AML. We evaluated the influence of secondary mutations on AML progression using the MLL-ENL model. This work revealed that, similar to human leukemia with MLL rearrangements, few secondary driver mutations could be identified. When present, secondary mutations converge on the RAS/MAPK; which is well-established also for human MLL-rearranged AML. We were able to demonstrate that the order of mutations has an influence of disease progression, such that when an activating RAS mutation precedes MLL-ENL onset, this affects both latency and different subtypes of leukemia developing.
We explored the well-established concept of cancer cel restriction by host immunity. Again, these concepts have almost exclusively been confined to models of solid cancer. When evaluated in an MLL-ENL AML setting, we could find little evidence that host immunity is a significant barrier to AML development. However, we could clearly observe a role for host immunity upon establishment of leukemia, arguing for the the use of (refined) immunotherapies in MLL-fusion associated AML.
Finally, we have taken dual approach to study both normal and malignant hematopoiesis. A first central question related to the general concept of hematopoietic stem cell ageing. Given the findings from Aim 1 that mutation order might be central for disease progression of AML, we hypothesised that chronological ageing might be underwritten by defined mutations (as has also been suggested in recent work on aged human hematopoiesis). Within the project, we developed an experimental strategy allowing us to convert functionally aged stem cells into iPS cells, followed by the generation of chimeric mice via blastocysts complementations. Counter to our hypothesis, this has revealed aged somatic donor hematopoietic stem cells could be reverted into stem cells with young functional and molecular properties. In more direct work on the influence of ageing on MLL-ENL development, we have recently established that the general poor regenerative properties of ageing hematopoiesis also translates into a poor competence for leukemia-initiation.