Co-culture model of B-cell acute lymphoblastic leukemia recapitulates a transcription signature of chemotherapy-refractory minimal residual disease

ABSTRACT: B-cell acute lymphoblastic leukemia (ALL) develops when immature B cells stop differentiating and begin rapidly proliferating, allowing for an accumulation of immature cells in the bone marrow as well as the periphery. The bone marrow is a well-established sanctuary site, and while standard of care treatments allows for complete remission in most patients, a small population of patients will relapse, likely due to the presence of minimal residual disease (MRD) consisting of a dormant, chemotherapy-resistant cell population. We developed an in vitro cell culture model in which human ALL cells are grown in co-culture with either bone marrow-derived stromal cells or human osteoblasts. Within this culture, tumor cells can either be found in suspension, lightly attached to the top of the adherent cells, or buried under the adherent cells in a population that is phase dim (PD) by light microscopy. We have characterized the PD cells as being both a dormant and chemo-resistant cell population that relies heavily on glycolysis for energy. Additionally, we found that this model can be used to recapitulate MRD in vitro, as a means to identify and test novel therapeutics and treatment strategies that would allow for complete eradication of the disease from the bone marrow. In the current study, we characterized the transcriptional signature of the PD cells using RNA-Seq analysis, and this data was also compared to a published data set of human MRD B-ALL patients. Our RNA-Seq analyses showed that the PD cell population from the in vitro co-culture model closely mimics MRD expression patterns in patients. These findings suggest that our in vitro system can be used as a model for mimicking MRD. Furthermore, we identified both genes and key signaling pathways that were common between the PD cells and patient MRD that can provide us with potential therapeutic targets leading to a better outcome for the subset of patients that relapse.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148520 | GEO | 2021/08/06

REPOSITORIES: GEO