Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML)

Djamai, Hanane; Berrou, Jeannig; Dupont, Mélanie; Coudé, Marie-Magdelaine; Delord, Marc; Clappier, Emmanuelle; Marceau-Renaut, Alice; Kaci, Anna; Raffoux, Emmanuel; Itzykson, Raphaël; Berthier, Christine; Wu, Hsin-Chieh; Hleihel, Rita; Bazarbachi, Ali; Baruchel, André; Gardin, Claude; Dombret, Hervé; Braun, Thorsten

doi:10.3390/biomedicines9111704

Cited by 7 publications

(6 citation statements)

References 31 publications

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“…Venetoclax alone, or combined to low intensity chemotherapy, Arsenic or menin inhibitors proved efficient in preclinical and more importantly in different categories of NPM1c AML patients including those with minimal residual disease, or relapsed refractory patients [ 29 , 30 , 50 , 51 , 52 , 53 ]. BET-inhibitors also induced differentiation and apoptosis in NPM1c cells following induced proteasome-dependent degradation of NPM1c [ 54 ]. In line with these findings, we demonstrated that EAPB0503, induced the selective growth arrest and apoptosis in NPM1c AML cells following NPM1c proteasomal degradation [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

EAPB0503, an Imidazoquinoxaline Derivative Modulates SENP3/ARF Mediated SUMOylation, and Induces NPM1c Degradation in NPM1 Mutant AML

Skayneh

Jishi

Hleihel

et al. 2022

IJMS

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Nucleophosmin-1 (NPM1) is a pleiotropic protein involved in numerous cellular processes. NPM1 shuttles between the nucleus and the cytoplasm, but exhibits a predominant nucleolar localization, where its fate and functions are exquisitely controlled by dynamic post-translational modifications (PTM). Sentrin/SUMO Specific Peptidase 3 (SENP3) and ARF are two nucleolar proteins involved in NPM1 PTMs. SENP3 antagonizes ARF-mediated NPM1 SUMOylation, to promote ribosomal biogenesis. In Acute Myeloid Leukemia (AML), NPM1 is frequently mutated, and exhibits an aberrant cytoplasmic localization (NPM1c). NPM1c mutations define a separate AML entity with good prognosis in some AML patients, rendering NPM1c as a potential therapeutic target. SENP3-mediated NPM1 de-SUMOylation induces resistance to therapy in NPM1c AML. Here, we demonstrate that the imidazoquinoxaline EAPB0503 prolongs the survival and results in selective reduction in the leukemia burden of NPM1c AML xenograft mice. Indeed, EAPB0503 selectively downregulates HDM2 expression and activates the p53 pathway in NPM1c expressing cells, resulting in apoptosis. Importantly, we unraveled that NPM1c expressing cells exhibit low basal levels of SUMOylation paralleled with high SENP3 and low ARF basal levels. EAPB0503 reverted these molecular players by inducing NPM1c SUMOylation and ubiquitylation, leading to its proteasomal degradation. EAPB0503-induced NPM1c SUMOylation is concurrent with SENP3 downregulation and ARF upregulation in NPM1c expressing cells. Collectively, these results provide a strong rationale for testing therapies modulating NPM1c post-translational modifications in the management of NPM1c AML.

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Section: Discussionmentioning

confidence: 99%

EAPB0503, an Imidazoquinoxaline Derivative Modulates SENP3/ARF Mediated SUMOylation, and Induces NPM1c Degradation in NPM1 Mutant AML

Skayneh

Jishi

Hleihel

et al. 2022

IJMS

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“…These results provide a promising epigenetic therapy target for pediatric AML. Other BET inhibitors, including MK-8628 (OTX015) and CPI-0610, also are now being evaluated in phase 1 and 2 trials in adult AML (NCT02698189, NCT02158858) ( 101 ).…”

Section: Epigenetic Targeted Therapy In Pediatric Acute Myeloid Leukemiamentioning

confidence: 99%

Epigenetic modifications and targeted therapy in pediatric acute myeloid leukemia

Wen

Jin

et al. 2022

Front. Pediatr.

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Acute myeloid leukemia (AML) is a hematological malignancy resulting from the genetic alterations and epigenetic dysregulations of the hematopoietic progenitor cells. One-third of children with AML remain at risk of relapse even though outcomes have improved in recent decades. Epigenetic dysregulations have been identified to play a significant role during myeloid leukemogenesis. In contrast to genetic changes, epigenetic modifications are typically reversible, opening the door to the development of epigenetic targeted therapy. In this review, we provide an overview of the landscape of epigenetic alterations and describe the current progress that has been made in epigenetic targeted therapy, and pay close attention to the potential value of epigenetic abnormalities in the precision and combinational therapy of pediatric AML.

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“…These results provide a promising epigenetic therapy target for pediatric AML. Other BET inhibitors, including MK-8628 (OTX015) and CPI-0610, also are currently being assessed in phase 1 and 2 trials in adult patients with AML (NCT02698189, NCT02158858) [101].…”

Section: Dot1l Inhibitorsmentioning

confidence: 99%

Epigenetic Modifications and Targeted Therapy in Pediatric Acute Myeloid Leukemia

Xu¹,

Wen²,

Jin³

et al. 2022

Preprint

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Acute myeloid leukemia (AML) is a hematological malignancy that is the culmination of genetic and epigenetic alterations in the hematopoietic progenitor cells, leading to uncontrolled proliferation at the expense of normal hematopoiesis and bone marrow exhaustion. Although the outcomes for pediatric AML have improved in recent decades, at least one third of children still have relapses. Recent studies have notably highlighted the important role of dysregulated epi-genetic mechanisms in myeloid leukemogenesis. Epigenetic modifications are frequently reversible compared to genetic alterations, thus providing opportunities for targeted epigenetic therapy. In this review, we summarize the landscape of epigenetic alterations and the progress to date in epigenetic targeted therapy, and focus on the future role of epigenetic abnormalities in predicting relapse and the precision therapy in pediatric AML.

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Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML)

Cited by 7 publications

References 31 publications

EAPB0503, an Imidazoquinoxaline Derivative Modulates SENP3/ARF Mediated SUMOylation, and Induces NPM1c Degradation in NPM1 Mutant AML

EAPB0503, an Imidazoquinoxaline Derivative Modulates SENP3/ARF Mediated SUMOylation, and Induces NPM1c Degradation in NPM1 Mutant AML

Epigenetic modifications and targeted therapy in pediatric acute myeloid leukemia

Epigenetic Modifications and Targeted Therapy in Pediatric Acute Myeloid Leukemia

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