A multiparametric niche-like drug screening platform in acute myeloid leukemia.
Blood Cancer J
; 12(6): 95, 2022 06 24.
Article
in En
| MEDLINE
| ID: mdl-35750691
Functional precision medicine in AML often relies on short-term in vitro drug sensitivity screening (DSS) of primary patient cells in standard culture conditions. We designed a niche-like DSS assay combining physiologic hypoxia (O2 3%) and mesenchymal stromal cell (MSC) co-culture with multiparameter flow cytometry to enumerate lymphocytes and differentiating (CD11/CD14/CD15+) or leukemic stem cell (LSC)-enriched (GPR56+) cells within the leukemic bulk. After functional validation of GPR56 expression as a surrogate for LSC enrichment, the assay identified three patterns of response, including cytotoxicity on blasts sparing LSCs, induction of differentiation, and selective impairment of LSCs. We refined our niche-like culture by including plasma-like amino-acid and cytokine concentrations identified by targeted metabolomics and proteomics of primary AML bone marrow plasma samples. Systematic interrogation revealed distinct contributions of each niche-like component to leukemic outgrowth and drug response. Short-term niche-like culture preserved clonal architecture and transcriptional states of primary leukemic cells. In a cohort of 45 AML samples enriched for NPM1c AML, the niche-like multiparametric assay could predict morphologically (p = 0.02) and molecular (NPM1c MRD, p = 0.04) response to anthracycline-cytarabine induction chemotherapy. In this cohort, a 23-drug screen nominated ruxolitinib as a sensitizer to anthracycline-cytarabine. This finding was validated in an NPM1c PDX model.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Leukemia, Myeloid, Acute
/
Mesenchymal Stem Cells
Type of study:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Limits:
Humans
Language:
En
Journal:
Blood Cancer J
Year:
2022
Document type:
Article
Affiliation country:
Country of publication: