Leukemia-on-a-chip: Dissecting the chemoresistance mechanisms in B cell acute lymphoblastic leukemia bone marrow niche

Chao Ma, Matthew T. Witkowski, Jacob Harris, Igor Dolgalev, Sheetal Sreeram, Weiyi Qian, Jie Tong, Xin Chen, Iannis Aifantis, Weiqiang Chen

Research output: Contribution to journalArticlepeer-review

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 "leukemiaon- 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.

Original languageEnglish (US)
Article numberaba5536
JournalScience Advances
Volume6
Issue number44
DOIs
StatePublished - Oct 28 2020

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Leukemia-on-a-chip: Dissecting the chemoresistance mechanisms in B cell acute lymphoblastic leukemia bone marrow niche'. Together they form a unique fingerprint.

Cite this