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Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML)
Hanane Djamai1, Jeannig Berrou1, Mélanie Dupont1
1Laboratoire de Transfert des Leucémies, URP-3518, Institut de Recherche Saint Louis, Université de Paris, 75010 Paris, France.
Abstract:
BET inhibitors (BETi) including OTX015 (MK-8628) and JQ1 demonstrated antileukemic activity including NPM1c AML cells. Nevertheless, the biological consequences of BETi in NPM1c AML were not fully investigated. Even if of better prognosis AML patients with NPM1c may relapse and treatment remains difficult. Differentiation-based therapy by all trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) demonstrated activity in NPM1c AML. We found that BETi, similar to ATO + ATRA, induced differentiation and apoptosis which was TP53 independent in the NPM1c cell line OCI-AML3 and primary cells. Furthermore, BETi induced proteasome-dependent degradation of NPM1c. BETi degraded NPM1c in the cytosol while BRD4 is degraded in the nucleus which suggests that restoration of the NPM1/BRD4 equilibrium in the nucleus of NPM1c cells is essential for the efficacy of BETi. While ATO + ATRA had significant biological activity in NPM1c IMS-M2 cell line, those cells were resistant to BETi. Gene profiling revealed that IMS-M2 cells probably resist to BETi by upregulation of LSC pathways independently of the downregulation of a core BET-responsive transcriptional program. ATO + ATRA downregulated a NPM1c specific HOX gene signature while anti-leukemic effects of BETi appear HOX gene independent. Our preclinical results encourage clinical testing of BETi in NPM1c AML patients.
Insights
BET inhibitors (BETi) induce differentiation and apoptosis in NPM1c AML cells, offering a promising new therapeutic avenue. These agents degrade NPM1c protein, suggesting a novel mechanism for treating relapsed or difficult AML cases.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- NPM1c-mutated acute myeloid leukemia (AML) can relapse despite initial good prognosis.
- Current treatments like ATRA + ATO show activity, but novel therapies are needed.
- The precise biological effects of BET inhibitors (BETi) in NPM1c AML require further investigation.
Purpose of the Study:
- To investigate the antileukemic mechanisms of BET inhibitors in NPM1c AML.
- To compare the efficacy and mechanisms of BETi with ATRA + ATO therapy.
- To identify potential resistance mechanisms to BETi in NPM1c AML.
Main Methods:
- Treatment of NPM1c AML cell lines (OCI-AML3, IMS-M2) and primary cells with BETi (OTX015, JQ1) and ATRA + ATO.
- Assessment of cellular differentiation, apoptosis, and protein degradation (NPM1c, BRD4).
- Gene expression profiling to identify molecular pathways and resistance mechanisms.
Main Results:
- BETi induced TP53-independent differentiation and apoptosis in NPM1c AML cells, similar to ATRA + ATO.
- BETi caused proteasome-dependent degradation of NPM1c in the cytosol and BRD4 in the nucleus.
- IMS-M2 cells, resistant to BETi, showed upregulation of LSC pathways, while ATRA + ATO was effective.
- BETi's anti-leukemic effects were HOX gene independent, unlike ATRA + ATO.
Conclusions:
- BETi demonstrate significant antileukemic activity in NPM1c AML through NPM1c degradation and induction of differentiation.
- Restoring the NPM1/BRD4 nuclear equilibrium is crucial for BETi efficacy.
- Upregulation of LSC pathways may confer resistance to BETi in certain NPM1c AML subtypes.
- Preclinical data support the clinical evaluation of BETi for NPM1c AML patients.
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