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In vivo RNAi screening identifies Pafah1b3 as a target for combination therapy with TKIs in BCR-ABL1 BCP-ALL
Eleanor R C Fiedler1, Arjun Bhutkar1, Emily Lawler1
1The Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA.
Abstract:
Despite the addition of tyrosine kinase inhibitors (TKIs) to the treatment of patients with BCR-ABL1 B-cell precursor acute lymphoblastic leukemia (BCR-ABL1 BCP-ALL), relapse both with and without BCR-ABL1 mutations is a persistent clinical problem. To identify BCR-ABL1-independent genetic mediators of response to the TKI dasatinib, we performed in vivo and in vitro RNA interference (RNAi) screens in a transplantable syngeneic mouse model of BCR-ABL1 BCP-ALL. By using a novel combination of a longitudinal screen design and independent component analysis of screening data, we identified hairpins that have distinct behavior in different therapeutic contexts as well as in the in vivo vs in vitro settings. In the set of genes whose loss sensitized BCR-ABL1 BCP-ALL cells to dasatinib, we identified Pafah1b3, which regulates intracellular levels of platelet-activating factor (PAF), as an in vivo-specific mediator of therapeutic response. Pafah1b3 loss significantly sensitized leukemia cells to the multiple TKIs, indicating that inhibition of PAFAH1B3 in combination with TKI treatment may be an effective therapeutic strategy for BCR-ABL1+ BCP-ALL patients. PAF-induced cell death as well as surface levels of PAF receptor (PAFR) in our model are altered upon dasatinib treatment and depend on the local leukemia microenvironment; the response of Pafah1b3 KO vs overexpressing cells to dasatinib is also dependent on microenvironmental context. Antagonism of the PAFR partially reverses the observed sensitization to TKI treatment upon Pafah1b3 loss in vivo, suggesting that signaling via the PAF/PAFR pathway is at least partially responsible for this effect.
Insights
Relapse in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) persists despite tyrosine kinase inhibitor (TKI) therapy. Researchers identified Pafah1b3 as a key mediator that sensitizes leukemia cells to TKIs, suggesting a novel combination therapy approach.
Area of Science:
- Hematology and Oncology
- Molecular Biology
- Pharmacology
Background:
- Relapse remains a significant challenge in treating Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (BCR-ABL1+ BCP-ALL), even with tyrosine kinase inhibitor (TKI) therapy.
- Identifying genetic factors that influence TKI response independently of BCR-ABL1 mutations is crucial for developing more effective treatment strategies.
- Understanding the interplay between leukemia cells and their microenvironment is essential for deciphering drug resistance mechanisms.
Purpose of the Study:
- To identify novel, BCR-ABL1-independent genetic mediators that influence response to the TKI dasatinib in BCR-ABL1+ BCP-ALL.
- To investigate the role of identified genes in mediating sensitivity or resistance to TKIs in both in vivo and in vitro settings.
- To explore the potential of targeting identified pathways, such as the platelet-activating factor (PAF) pathway, in combination with TKIs.
Main Methods:
- Performed in vivo and in vitro RNA interference (RNAi) screens using a transplantable syngeneic mouse model of BCR-ABL1+ BCP-ALL.
- Employed a longitudinal screen design and independent component analysis to identify genes with distinct behaviors across different contexts.
- Investigated the role of the identified gene Pafah1b3 in regulating PAF levels and its impact on TKI sensitivity, including interactions with the PAF receptor (PAFR) and the leukemia microenvironment.
Main Results:
- Identified Pafah1b3, a regulator of intracellular platelet-activating factor (PAF), as an in vivo-specific mediator that sensitizes BCR-ABL1+ BCP-ALL cells to dasatinib.
- Demonstrated that loss of Pafah1b3 significantly enhances sensitivity to multiple TKIs, suggesting a broad therapeutic potential.
- Showed that dasatinib treatment alters PAF-induced cell death and PAF receptor (PAFR) surface levels, with responses dependent on the leukemia microenvironment and Pafah1b3 expression levels. PAFR antagonism partially reversed TKI sensitization upon Pafah1b3 loss.
Conclusions:
- Pafah1b3 acts as a critical mediator of TKI response in BCR-ABL1+ BCP-ALL, particularly in an in vivo context.
- Inhibition of PAFAH1B3 in combination with TKI therapy represents a promising novel therapeutic strategy for patients with BCR-ABL1+ BCP-ALL.
- The PAF/PAFR signaling pathway is implicated in mediating TKI sensitivity and resistance, highlighting its potential as a therapeutic target in conjunction with TKIs.
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