T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments

Here, leukaemia cells are followed by intravital microscopy as they infiltrate mouse bone marrow and respond to chemotherapy, revealing that at all stages analysed they are highly motile and do not display any associations with particular bone marrow sub-compartments. Cancer cells are thought to rely on tight interactions with their micro-environment for survival. Using intravital microscopy, Cristina Lo Celso and colleagues have followed leukaemia cells isolated from a human T-cell acute lymphoblastic leukaemia (T-ALL) in a mouse model. The cells were implanted in mouse bone marrow. Surprisingly, they observe that leukaemia cells are highly motile and do not display any association with a particular sub-compartment of the bone marrow microenvironment. The leukaemia cells caused a disruption of the bone marrow itself, however, resulting in a loss of osteoblasts. It is widely accepted that complex interactions between cancer cells and their surrounding microenvironment contribute to disease development, chemo-resistance and disease relapse. In light of this observed interdependency, novel therapeutic interventions that target specific cancer stroma cell lineages and their interactions are being sought. Here we studied a mouse model of human T-cell acute lymphoblastic leukaemia (T-ALL) and used intravital microscopy to monitor the progression of disease within the bone marrow at both the tissue-wide and single-cell level over time, from bone marrow seeding to development/selection of chemo-resistance. We observed highly dynamic cellular interactions and promiscuous distribution of leukaemia cells that migrated across the bone marrow, without showing any preferential association with bone marrow sub-compartments. Unexpectedly, this behaviour was maintained throughout disease development, from the earliest bone marrow seeding to response and resistance to chemotherapy. Our results reveal that T-ALL cells do not depend on specific bone marrow microenvironments for propagation of disease, nor for the selection of chemo-resistant clones, suggesting that a stochastic mechanism underlies these processes. Yet, although T-ALL infiltration and progression are independent of the stroma, accumulated disease burden leads to rapid, selective remodelling of the endosteal space, resulting in a complete loss of mature osteoblastic cells while perivascular cells are maintained. This outcome leads to a shift in the balance of endogenous bone marrow stroma, towards a composition associated with less efficient haematopoietic stem cell function1. This novel, dynamic analysis of T-ALL interactions with the bone marrow microenvironment in vivo, supported by evidence from human T-ALL samples, highlights that future therapeutic interventions should target the migration and promiscuous interactions of cancer cells with the surrounding microenvironment, rather than specific bone marrow stroma, to combat the invasion by and survival of chemo-resistant T-ALL cells.