It is widely accepted that complex interactions between blood cells and their surrounding microenvironments contribute to homeostatic cell function and disease development. In light of this interdependency, novel interventions that target specific stromal cell lineages and their interactions with blood cell subsets in disease are being investigated. To investigate this, we are studying mouse and humanised models of autoimmunity, hematological malignancies and protective immunity. We have developed intravital microscopy methods that allow us to monitor the same cells and microenvironments in the bone marrow (BM) and peripheral immune organs long-term including repeated imaging sessions over multiple days. Using this approach, we have observed lineage specific interactions of haematopoetic cells with stroma and microenvironments in the BM. For example, we observed highly dynamic interactions and promiscuous distribution of T-ALL cells throughout the BM, without any preferential association with microenvironments. Unexpectedly, this environment-agnostic behaviour was maintained during development of chemotherapy resistance. Interestingly, this behavior is not a conserved feature of blood cells from other immune cell lineages.
Our results reveal that T-ALL does not depend on specific microenvironments for propagation of disease, nor the selection of chemo-resistant clones, suggesting a stochastic mechanism underlies these processes. Yet, while progression is independent of the stroma, accumulation of malignant lymphocytes leads to rapid, selective remodeling of the endosteal space, resulting in a complete loss of mature osteoblastic cells. This outcome shifts the balance of endogenous BM stroma towards a composition associated with less efficient hematopoiesis. However, we observe lineage specific tissue remodeling hardwired to the origin of the malignant cells. This novel, dynamic analysis highlights that future therapeutic interventions should target cell-specific mechanisms, in order to combat the invasion and survival of pathogenic blood cells. These studies provide the foundation for future studies investigating the metastasis of other tumours as well as homeostatic hematopoiesis.