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

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

PROVIDER: PRJNA624866 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11539200_1.fastq.gz	Fastqsanger.gz
	SRR11539200_2.fastq.gz	Fastqsanger.gz
	SRR11539201_1.fastq.gz	Fastqsanger.gz
	SRR11539201_2.fastq.gz	Fastqsanger.gz
	SRR11539178_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

2021-08-06 | GSE148520 | GEO

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

Project description:B-cell acute lymphoblastic leukemia (ALL) is characterized by accumulation of immature hematopoietic cells in the bone marrow, a well-established sanctuary site for leukemic cell survival during treatment. While standard of care treatment results in remission in most patients, a small population of patients will relapse, due to the presence of minimal residual disease (MRD) consisting of dormant, chemotherapy-resistant tumor cells. To interrogate this clinically relevant population of treatment refractory cells, we developed an in vitro cell model in which human ALL cells are grown in co-culture with human derived bone marrow stromal cells or osteoblasts. Within this co-culture, tumor cells are 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. PD cells are dormant and chemotherapy-resistant, consistent with the population of cells that underlies MRD. In the current study, we characterized the transcriptional signature of PD cells by RNA-Seq, and these data were compared to a published expression data set derived from human MRD B-cell ALL patients. Our comparative analyses revealed that the PD cell population is markedly similar to the MRD expression patterns from the primary cells isolated from patients. We further identified genes and key signaling pathways that are common between the PD tumor cells from co-culture and patient derived MRD cells as potential therapeutic targets for future studies.

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Proteomic Alterations Associated with Residual Disease in Neoadjuvant Chemotherapy Treated Ovarian Cancer Tissues

Project description:Optimal cytoreduction to no residual disease (R0) correlates with improved disease outcome in the management of high-grade serous ovarian cancer (HGSOC) patients. Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) offers an alternate approach to management of HGSOC patients to achieve complete resection. This study assessed proteomic alterations in matched, chemotherapy naïve and NACT-treated patients tumors obtained from HGSOC patients with suboptimal (R1) versus optimal (R0) debulking at IDS. We describe distinct proteome profiles in pre- and post-NACT HGSOC tumors correlating with residual disease status providing prognostic biomarkers for residual disease at IDS as well as candidate proteins associated with NACT resistance warranting further pre-clinical investigation.

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2021-10-06 | GSE137359 | GEO

New markers for minimal residual disease detection in acute lymphoblastic leukemia

Project description:To identify new markers for minimal residual disease (MRD) detection in acute lymphoblastic leukemia (ALL), we compared genome-wide gene expression of lymphoblasts from 270 patients with newly diagnosed childhood ALL to that of normal CD19 CD10 B-cell progenitors (n=4). Expression of 30 genes differentially expressed by > 3-fold in at least 25% of cases of ALL (or 40% of ALL subtypes) was tested by flow cytometry in 200 B-lineage ALL and 61 nonleukemic BM samples, including samples containing hematogones. Of the 30 markers, 22 (CD44, BCL2, HSPB1, CD73, CD24, CD123, CD72, CD86, CD200, CD79b, CD164, CD304, CD97, CD102, CD99, CD300a, CD130, PBX1, CTNNA1, ITGB7, CD69, CD49f) were differentially expressed in up to 81.4% of ALL cases; expression of some markers was associated with the presence of genetic abnormalities. Results of MRD detection by flow cytometry with these markers correlated well with those of molecular testing (52 follow-up samples from 18 patients); sequential studies during treatment and diagnosis-relapse comparisons documented their stability. When incorporated in 6-marker combinations, the new markers afforded the detection of 1 leukemic cell among 105 BM cells. These new markers should allow MRD studies in all B-lineage ALL patients, and substantially improve their sensitivity.

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