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| Status |
Public on Oct 31, 2020 |
| Title |
Leukemia-on-a-Chip: Dissecting the chemo-resistance mechanisms in B-cell acute lymphoblastic leukemia (B-ALL) bone marrow niche |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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-κB 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.
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| 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
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| Contributor(s) |
Witkowski MT, Dolgalev I, Aifantis I, Ma C, Chen W |
| Citation(s) |
33127669, 37131801 |
| Submission date |
Oct 14, 2019 |
| Last update date |
Aug 02, 2023 |
| Contact name |
Igor Dolgalev |
| Organization name |
NYU Grossman School of Medicine
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| Street address |
550 1st Ave
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| City |
New York |
| State/province |
New York |
| ZIP/Postal code |
10016 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (2) |
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| Relations |
| BioProject |
PRJNA577411 |
| SRA |
SRP225514 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE138811_RAW.tar |
409.1 Mb |
(http)(custom) |
TAR (of MTX, TSV) |
| GSE138811_barcode_sample_metadata.txt.gz |
822 b |
(ftp)(http) |
TXT |
| GSE138811_barcodes.tsv.gz |
20.0 Mb |
(ftp)(http) |
TSV |
| GSE138811_counts.normalized.csv.gz |
134.9 Mb |
(ftp)(http) |
CSV |
| GSE138811_counts.raw.csv.gz |
46.5 Mb |
(ftp)(http) |
CSV |
| GSE138811_features.tsv.gz |
297.6 Kb |
(ftp)(http) |
TSV |
| GSE138811_metadata.csv.gz |
316.2 Kb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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