Intravital Microscopy Reveals Fundamental Differences in the Interaction of Stem Cells and T Acute Lymphoblastic Leukaemia with the Bone Marrow Microenvironment

Haematopoiesis is the complex developmental process maintaining the turnover of all blood cell lineages, i.e. erythrocytes, immune (white) cells and platelets. It takes place primarily in the bone marrow, where it critically depends on the correct functioning of rare, quiescent haematopoietic stem cells (HSCs) and more numerous HSC-derived, highly proliferative and differentiating haematopoietic progenitor cells (HPCs). This is regulated by complex interactions between stem cells and the bone marrow microenvironment, and it was suggested to change in settings involving stress. Indeed, using intravital microscopy, we previously showed that HSCs injected in irradiated recipients steadily engage with endosteal niches. Moreover, if phenotypically identical HSCs are harvested from mice harbouring a natural infection, such as that caused by T.spiralis, they show a unique 'stop and go' migratory behaviour, engage larger niches, yet remain in the proximity of osteoblastic cells. Based on these and other studies, it has been hypothesised that also malignant haematopoietic cells rely on interactions with specific bone marrow microenvironments to grow, and especially to develop chemoresistance. To investigate this further, we performed longitudinal imaging of mice injected with murine and human T acute lymphoblastic leukaemia (T-ALL) cells over the course of hours or days, including during response to multiple chemotherapy treatments. Strikingly, we observed a very different behaviour from that of HSCs, with T-ALL cells showing a highly migratory behaviour throughout all stages of disease, from initial bone marrow infiltration to response to chemotherapy. Interestingly, in untreated mice and in patients trephine biopsies we observed rapid loss of osteoblastic cells by apoptosis, an event that likely contributes to the dramatic loss of healthy haematopoiesis observed in mice and patients. Together, these finds indicate that novel therapeutic strategies should target the ability of T-ALL cells to entertain short-lived and promiscuous interactions with any neighbouring cells, and aim to strengthen the bone marrow microenvironment to improve support for residual healthy haematopoiesis. Disclosures Harrison: AbbVie: Research Funding; Janssen Cilag: Research Funding, Speakers Bureau. Quach: Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.