The spleen as a sanctuary site for residual leukemic cells following ABT-199 monotherapy in ETP-ALL
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA708347 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13919690.fastq.gz | Fastqsanger.gz | |||
| SRR13919691.fastq.gz | Fastqsanger.gz | |||
| SRR13919692.fastq.gz | Fastqsanger.gz | |||
| SRR13919693.fastq.gz | Fastqsanger.gz |
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Project description:Two mice in which luciferase-positive LOUCY ETP-ALL cells were xenografted were treated with either vehicle or ABT-199 (50 mg/kg) for 11 days. Afterwards, single cells suspensions were made from bone marrow and spleen of both mice for 10x Genomics scRNA-seq. Following quality control, a total of 13,681 spleen cells and 11,442 bone marrow cells of the control mouse and 15,955 spleen cells and 9,443 bone marrow cells of the ABT 199 treated mouse were processed for further analysis. Our data show that ABT-199 triggers transcriptional changes in T-cell differentiation genes in leukemic cells obtained from the spleen microenvironment. These results are in line with our previous findings that mature typical T-ALL are resistant to ABT-199.
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Project description:Genome wide DNA methylation profiling of parental, ABT-199 resistant population, and ABT-199 resistant clones from 3 acute myelogenous leukemia (AML) cell lines (MOLM-13, MV-4-11, OCI-AMLO2). The Illumina Infinium MethylationEPIC Human DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpGs from AML cell line samples. Samples include 4 ABT-199 sensitive parental MOLM-13 population samples, 4 ABT-199 resistant MOLM-13 population samples, 3 ABT-199 resistant MOLM-13 S2 clone samples, 3 ABT-199 resistant MOLM-13 S5 clone samples, 4 ABT-199 resistant MOLM-13 S6 clone samples, 3 ABT-199 sensitive parental MV-4-11 population samples, 3 ABT-199 resistant MV-4-11 population samples, 3 ABT-199 sensitive parental OCI-AML2 population samples, 3 ABT-199 resistant OCI-AML2 population samples, 3 ABT-199 resistant OCI-AML2 S1 clone samples, 3 ABT-199 resistant OCI-AML2 S2 clone samples, 3 ABT-199 resistant OCI-AML2 S8 clone samples.
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Project description:B-cell lymphoma 2 (BCL-2) has recently emerged as a therapeutic target for early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL), a high-risk subtype of human T-cell ALL. The major clinical challenge with targeted therapeutics, such as the BCL-2 inhibitor ABT-199, is the development of acquired resistance. We assessed the in vivo response of luciferase-positive LOUCY cells to ABT-199 monotherapy and observed specific residual disease in the splenic microenvironment. Of note, these results were confirmed by using a primary ETP-ALL patient-derived xenograft. Splenomegaly has previously been associated with poor prognosis in diverse types of leukemia. However, the exact mechanism by which the splenic microenvironment alters responses to specific targeted therapies remains largely unexplored. We show that residual LOUCY cells isolated from the spleen microenvironment displayed reduced BCL-2 dependence, which was accompanied by decreased BCL-2 expression levels. Notably, this phenotype of reduced BCL-2 dependence could be recapitulated by using human splenic fibroblast coculture experiments and was confirmed in an in vitro chronic ABT-199 resistance model of LOUCY. Finally, single-cell RNA-sequencing was used to show that ABT-199 triggers transcriptional changes in T-cell differentiation genes in leukemic cells obtained from the spleen microenvironment. Of note, increased expression of CD1a and sCD3 was also observed in ABT199-resistant LOUCY clones, further reinforcing the idea that a more differentiated leukemic population might display decreased sensitivity toward BCL-2 inhibition. Overall, our data reveal the spleen as a site of residual disease for ABT-199 treatment in ETP-ALL and provide evidence for plasticity in T-cell differentiation as a mechanism of therapy resistance.
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Project description:Drug-tolerant “persister” tumor cells underlie the emergence of drug-resistant clones contribute to relapse and disease progression; thus, identifying actionable targets that disable persisters and mitigate relapse are a high priority need. Although the BCL2-targeting agent venetoclax (ABT-199) has shown promising responses in mantle cell and double hit B cell lymphomas, resistance often arises, yet mechanistically how this occurs is unclear. Here we report that ABT-199 resistance can evolve from persister clones that have selective deletions at 18q21 that involve the drug target BCL2 and the apoptotic regulators Noxa (PMAIP1) and TCF4. Notably, reprogramming of super enhancers (SE) in persisters contributes to resistance, where there is a selection for SE-directed overexpression of the apoptotic regulator BCL2A1 and oncogenic transcription factors IKZF1 and FOXC1. At the same time, the SE reprogramming confers an opportunity for overcoming ABT-199 resistance. An unbiased drug screen on a platform that recapitulates the lymphoma microenvironment revealed that persisters are vulnerable to inhibitors of transcription initiation and elongation, and especially so to inhibitors of cyclin-dependent kinase 7 (CDK7) that is essential for transcription initiation. Specifically, CDK7 loss or inhibition eliminated the persister phenotype by disabling SE-driven expression of BCL2A1, IKZF1 and FOXC1. Thus, the co-treatment of ABT-199 with CDK7 inhibitors blocked the evolution of drug resistance, and provoked tumor regression in models of mantle cell lymphoma (MCL) and double hit lymphomas (DHL) that overexpress both MYC and BCL2. Together, these findings establish loss of apoptotic regulators and an adaptive transcriptional response as drug resistance mechanisms in lymphoma, more importantly, establish a rationale for transcription inhibition-based combination strategies to prevent and overcome drug resistance in B cell malignancies toward BCL2 inhibitor.
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Project description:Drug-tolerant “persister” cells underlie the emergence of drug-resistant clones and allow residual tumors to survive therapy; thus, represent an attractive therapeutic target to mitigate relapse. With the promising outcome, yet some resistance cases surfaced after the approval of venetoclax (ABT-199), we defined a novel invasive drug resistance mechanism induced by Bcl2 inhibitor via examining the evolution of drug tolerant persister clones generated with ABT-199 treatment. The ABT-199 drug-tolerant persister cells showed genetic alteration by losing the copy number at 18q21 paralleled with BCL2, PMAIP1 and TCF4 gene downregulation. The persister status are generated through major enhancer-remodeling mediated transcriptional activation of the super enhancer, which offered unique opportunity for overcoming the drug resistance. The insight of major determinant for ABT-199 persistence evolution identified the molecular vulnerability in Bcl2 inhibitor resistant lymphoma cells through CDK7 pathway inhibition. The combined CDK7 and BCL2 inhibition was found to be more effective against ABT-199 persistence ex vivo and in vivo rather than the parental line, and CDK7 inhibition eliminated the persister phenotype by blocking dynamic active enhancer formation to further prevent the evolution of drug resistance. Together, these studies unified genetic alteration and non-mutational adaptive response as a drug resistance mechanism, more importantly, demonstrated a rationale for transcriptional inhibition-based combination strategies to prevent and overcome drug resistance in B-cell malignancies.
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