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An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia
Birgit Knoechel1, Justine E Roderick2, Kaylyn E Williamson3
11] Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [4] Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [5].
Abstract:
The identification of activating NOTCH1 mutations in T cell acute lymphoblastic leukemia (T-ALL) led to clinical testing of γ-secretase inhibitors (GSIs) that prevent NOTCH1 activation. However, responses to these inhibitors have been transient, suggesting that resistance limits their clinical efficacy. Here we modeled T-ALL resistance, identifying GSI-tolerant 'persister' cells that expand in the absence of NOTCH1 signaling. Rare persisters are already present in naive T-ALL populations, and the reversibility of their phenotype suggests an epigenetic mechanism. Relative to GSI-sensitive cells, persister cells activate distinct signaling and transcriptional programs and exhibit chromatin compaction. A knockdown screen identified chromatin regulators essential for persister viability, including BRD4. BRD4 binds enhancers near critical T-ALL genes, including MYC and BCL2. The BRD4 inhibitor JQ1 downregulates expression of these targets and induces growth arrest and apoptosis in persister cells, at doses well tolerated by GSI-sensitive cells. Consistently, the GSI-JQ1 combination was found to be effective against primary human leukemias in vivo. Our findings establish a role for epigenetic heterogeneity in leukemia resistance that may be addressed by incorporating epigenetic modulators in combination therapy.
Insights
T cell acute lymphoblastic leukemia (T-ALL) resistance to NOTCH1 inhibitors involves epigenetic changes in persister cells. Targeting epigenetic regulator BRD4 with JQ1 overcomes this resistance, offering a new combination therapy approach.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Activating NOTCH1 mutations drive T cell acute lymphoblastic leukemia (T-ALL).
- γ-secretase inhibitors (GSIs) targeting NOTCH1 show transient efficacy due to resistance.
- Leukemia drug resistance necessitates understanding underlying mechanisms.
Purpose of the Study:
- To model and identify mechanisms of T-ALL resistance to GSIs.
- To investigate the role of epigenetic heterogeneity in GSI resistance.
- To explore therapeutic strategies targeting resistant leukemia cells.
Main Methods:
- Modeling T-ALL resistance to identify GSI-tolerant persister cells.
- Analyzing signaling, transcriptional programs, and chromatin structure in persister cells.
- Utilizing knockdown screens to identify essential regulators, including BRD4.
- Testing BRD4 inhibitor JQ1 and GSI-JQ1 combination therapy in vitro and in vivo.
Main Results:
- GSI-tolerant persister cells, present in naive T-ALL, exhibit epigenetic alterations and chromatin compaction.
- BRD4 was identified as crucial for persister cell viability, regulating MYC and BCL2 expression.
- JQ1 induced apoptosis in persister cells and was well-tolerated by GSI-sensitive cells.
- The combination of GSI and JQ1 demonstrated efficacy against primary human leukemias.
Conclusions:
- Epigenetic heterogeneity contributes significantly to T-ALL resistance against NOTCH1 inhibition.
- Targeting BRD4 with epigenetic modulators like JQ1 can overcome GSI resistance.
- Combination therapy involving GSIs and epigenetic modulators offers a promising strategy for T-ALL treatment.
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