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

Abstract

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. To this end, 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 a stochastic mechanism underlies these processes. Yet, while 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 whilst 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, in order to combat the invasion by and survival of chemo-resistant T-ALL cells.

Molecular mobility and activity in an intravital imaging setting – implications for cancer progression and targeting

“…Another study described the bone marrow seeding of leukaemia cells in vivo and their transient and promiscuous interactions with their microenvironment ( Fig. 2A; Hawkins et al, 2016). Here, IVM revealed a progressive remodelling of the bone marrow microenvironment during disease progression that was confirmed in biopsies from human patients, which emphasises the value of IVM in pre-clinical models to gain insights into disease aetiology (Hawkins et al, 2016).…”

Blood stem cells: from beginning to end

“…Cristina showed that during infection, HSCs become either motile (although not mobilized) or very still, and that the flux through HSC and progenitor (HSPC) populations is likely to be dramatically altered (Vainieri et al, 2016). Furthermore, results presented by Delfim Duarte from her laboratory highlighted the increasing migratory behavior of leukemia cells from early bone marrow infiltration to overt chemoresistance and their relationship with bone marrow niches known to maintain HSCs (Hawkins et al, 2016). In keeping with this theme, Paul Frenette (Albert Einstein College of Medicine, New York, USA) emphasized a complex interplay between niche cells and hematopoietic cells in the bone marrow under steady state conditions in the adult.…”

Neoplasms in the bone marrow niches: disturbance of the microecosystem

“…Instead, T-ALL cells exhibit promiscuous distribution in BM and dynamic interactions with BM microenvironments throughout disease development from the early BM seeding to response and resistance to chemotherapy [40]. And, thus, a stochastic mechanism underlying these processes is proposed (Fig.…”

“…Full infiltration of T-ALL in recipient BM caused dramatic shrinking, blebbing, and apoptosis of osteoblastic cells, and spared blood vessels and nestin + perivascular cells (Fig. 2c) [40].…”

“…Moving targets are certainly more difficult to be shot, although therapeutic interventions for T-ALL have been proposed to target the migration and promiscuous interactions of leukemic cells with the BM environment [40].…”