GSE138811
Leukemia-on-a-Chip: Dissecting the chemo-resistance mechanisms in B-cell acute lymphoblastic leukemia (B-ALL) bone marrow niche
B-cell acute lymphoblastic leukemia (B-ALL) blasts hijack the bone marrow (BM) microenvironment to form chemo-protective leukemic BM 'niches', facilitating chemo-resistance and, ultimately, disease relapse. However, the ability to dissect these evolving, complex interactions among distinct B-ALL subtypes and their varying BM niches is limited with current in vivo methods. Herein, we reconstituted an in vitro three-dimensional (3D) organotypic leukemic BM niche model using a 'Leukemia-on-a-Chip' platform and comparatively studied the spatial and genetic heterogeneity of the BM niche in regulating B-ALL chemotherapy resistance. By emulating the leukemia BM anatomy in vitro, we determined that the perivascular and endosteal niches, through providing cytokine (e.g. CXCL12) and adhesive (e.g. VCAM-1/OPN) signals, differentially enhance downstream leukemia-intrinsic NF-?B signaling to support B-ALL survival and regulate cell cycle-related signaling to promote dormancy, which following demonstrated the pre-clinical utility of this microphysiological system to screen concomitant niche-directed therapies. Furthermore, we revealed the heterogeneity across different B-ALL subtypes by mapping subtype-specific leukemia and niche signals with application of single-cell RNA sequencing and analysis, which may contribute to chemotherapy resistance and disease relapse. Together, these results validate that our Leukemia-on-a-Chip allows for real-time and controllable dissection of the dynamic and heterotypic interactions between leukemia blasts and their BM microenvironment, which may translate to personalized therapeutics screening and disease management. Overall design: Single-cell RNA-sequencing libraries of the retrived cells form the ex vivo human bone marrow niche models. Human REH B-ALL cells, Human SUP-B15, Human umbilical vein cells (HUVECs, Lonza), Human mesenchymal stem cells (hMSC, Lonza) and Human osteoblasts (hFOB 1.19, ATCC) were also sequenced as controls