B cell acute lymphoblastic leukemia (B-ALL) blasts hijack the bone marrow (BM) microenvironment to form chemoprotective leukemic BM “niches,” facilitating chemoresistance and, ultimately, disease relapse.

However, the ability to dissect these evolving, heterogeneous interactions among distinct B-ALL subtypes and their varying BM niches is limited with current in vivo methods. In this paper , New York University researchers demonstrated an in vitro organotypic “leukemia-on-a-chip” model to emulate the in vivo B-ALL BM pathology and comparatively studied the spatial and genetic heterogeneity of the BM niche in regulating B-ALL chemotherapy resistance, revealing the heterogeneous chemoresistance mechanisms across various B-ALL cell lines and patient-derived samples.

The healthy BM niche plays a vital role in regulating HSC fate and maintaining normal hematopoiesis, whereas in hematologic malignancies like acute leukemia, leukemic cells harness the BM niche to favor leukemia survival.

In vitro engineered organotypic leukemia-on-a-chip functions as a bona fide replicate of the in vivo BM tissue architecture. Specifically, it provides several methodological advantages including the capability of control over various biological parameters (e.g., cell type, concentration and composition, tissue architectural information, and extracellular matrix properties), real-time visualization of physiological and pathophysiological dynamics (e.g., cell proliferation and migration, cell fate, and direct and indirect intercellular communications) modulated by internal factors and external stimuli, and the easy setup and compatibility with highthroughput on-chip biological assays (e.g., molecular, cellular, and histological characterizations) and follow-up cell retrieval for in-depth genetic analyses (e.g., scRNA-seq)

Using this biomimetic niche model, the authors systematically explored the temporally dynamic interactions between B-ALL blasts and niche cells (i.e., vascular ECs, perivascular MSCs, and endosteal osteoblasts) and determined the distinct roles of different niche cells in regulating cytokine (e.g., CXCL12), intercellular adhesive signaling (e.g., VCAM-1 and OPN), and downstream B-ALL prosurvival NF-kB signaling, as well as cell proliferation (i.e., Ki67) and quiescence (i.e., p21) markers, which further demonstrated subtype-associated heterogeneity and treatment responses.

The two divergent extrinsic cytokine and intercellular adhesive signaling mechanisms both enhanced downstream leukemia-intrinsic NF-kB signaling, supporting the notion that niche-derived signaling events promote B-ALL survival.

Along with the cytokine signaling, adhesive signaling provided by the niche cells has been reported to promote leukemia progression and therapy resistance: ECs mainly promote leukemia survival via VCAM-1/VLA-4 axis,
while MSCs and osteoblasts may induce leukemia dormancy via OPN signaling.

BM microenvironment has a complex cellular composition and orchestrated interactions. The hematopoietic cells, such as monocyte, were also demonstrated to regulate the chemoresistance of B-ALL and other types of leukemia, which needs to be considered in detail to further improve the biomimicry of our system.

Recently, CAR T cells have emerged as a promising Food and Drug
Administration–approved immunotherapy for relapsed and refractory B-ALL; however, patient responses are largely unpredictable. A detailed understanding of the leukemic BM immune niche is also indispensable for improving CAR T cell therapy.

Furthermore, the preclinical use of descibed model tested niche-cotargeting
regimens, which may translate to patient-specific therapy screening and response prediction.

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