Leukemia-on-a-chip: Dissecting the chemoresistance mechanisms in B cell acute lymphoblastic leukemia bone marrow niche.
Sci Adv, 2020/10;6(44)
Ma C[1, 2], Witkowski MT[3, 4], Harris J[2], Dolgalev I[3, 4], Sreeram S[3], Qian W[1], Tong J[1], Chen X[1], Aifantis I[3, 4], Chen W[5, 2, 4]
Affiliations
PMID: 33127669DOI: 10.1126/sciadv.aba5536
Impact factor: 14.957
Abstract
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. Here, we 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. We revealed the heterogeneous chemoresistance mechanisms across various B-ALL cell lines and patient-derived samples. We showed that the leukemic perivascular, endosteal, and hematopoietic niche-derived factors maintain B-ALL survival and quiescence (e.g., CXCL12 cytokine signal, VCAM-1/OPN adhesive signals, and enhanced downstream leukemia-intrinsic NF-κB pathway). Furthermore, we demonstrated the preclinical use of our model to test niche-cotargeting regimens, which may translate to patient-specific therapy screening and response prediction.
MeSH terms
Bone Marrow; Drug Resistance, Neoplasm; Humans; Lab-On-A-Chip Devices; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Stem Cell Niche; Tumor Microenvironment
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