Dataset Information

The spleen as a sanctuary site for residual leukemic cells following ABT-199 monotherapy in ETP-ALL

ABSTRACT: 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE168594 | GEO | 2021/03/10

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

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.

Dataset Information

The spleen as a sanctuary site for residual leukemic cells following ABT-199 monotherapy in ETP-ALL

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure