Combinatorial treatment with menin and FLT3 inhibitors induces complete remission in AML models with activating FLT3 mutations

Miao, Hongzhi; Kim, Eungi; Chen, Dong; Purohit, Trupta; Kempińska, Katarzyna; Ropa, James; Kłossowski, Szymon; Trotman, Winifred; Danet-Desnoyers, Gwenn-ael; Cierpicki, Tomasz; Grembecka, Jolanta

doi:10.1182/blood.2020006575

Cited by 30 publications

(18 citation statements)

References 26 publications

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“…Findings here confirm this by demonstrating that treatment with the MI SNDX-5613 abrogated the development of AML in a PDX model of AML harboring MLL1-r and mtFLT3. Consistent with previous reports, our findings also demonstrate that MI treatment improves median and overall survival of mice with established AML due to MOLM13 cells [ 46 ].…”

Section: Discussionsupporting

confidence: 93%

Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

et al. 2022

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Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.

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Section: Discussionsupporting

confidence: 93%

Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

et al. 2022

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“…6I ; P = 0.0003) with a 53% increase in median survival over the vehicle-treated mice (32 vs. 49 days). We further assessed the activity of TDI-11055 in a second MLL -r PDX model derived from an AML patient sample harboring an MLL–ENL fusion ( 57 ). Treatment of mice with TDI-11055 (200 mg/kg, p.o., q.d.)…”

Section: Resultsmentioning

confidence: 99%

Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia

Liu

Alikarami

et al. 2022

Cancer Discovery

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The chromatin reader eleven-nineteen-leukemia (ENL) has been identified as a critical dependency in AML, but its therapeutic potential remains unclear. We describe a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-11055, which displaces ENL from chromatin by blocking its YEATS domain interaction with acylated histones. Cell lines and primary patient samples carrying MLL rearrangements or NPM1 mutations are responsive to TDI-11055. A CRISPR-Cas9-mediated mutagenesis screen uncovers an ENL mutation that confers resistance to TDI-11055, validating the compound’s on-target activity. TDI-11055 treatment rapidly decreases chromatin occupancy of ENL-associated complexes and impairs transcription elongation, leading to suppression of key oncogenic gene expression programs and induction of differentiation. In vivo treatment with TDI-11055 blocks disease progression in cell line and patient-derived xenograft models of MLL-rearranged and NPM1-mutated AML. Our results establish ENL displacement from chromatin as a promising epigenetic therapy for molecularly defined AML subsets and support clinical translation of this approach.

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“…Menin inhibitors was also combined with inhibitors of FLT3 (mutated in about 40% of NPM1-mutated AML [3]), demonstrating a synergistic effect that resulted in stronger cell growth inhibition, apoptosis and differentiation of AML blast cells [98] and induction of long-lasting CR in PDX mice models of NPM1-mutated/FLT3-ITD AML [99]. Menin inhibitors have been also combined with XPO1 inhibitors.…”

Section: Targeting the Mll-menin Complexmentioning

confidence: 99%

Current status and future perspectives in targeted therapy of NPM1-mutated AML

et al. 2022

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Nucleophosmin 1 (NPM1) is a nucleus-cytoplasmic shuttling protein which is predominantly located in the nucleolus and exerts multiple functions, including regulation of centrosome duplication, ribosome biogenesis and export, histone assembly, maintenance of genomic stability and response to nucleolar stress. NPM1 mutations are the most common genetic alteration in acute myeloid leukemia (AML), detected in about 30–35% of adult AML and more than 50% of AML with normal karyotype. Because of its peculiar molecular and clinico-pathological features, including aberrant cytoplasmic dislocation of the NPM1 mutant and wild-type proteins, lack of involvement in driving clonal hematopoiesis, mutual exclusion with recurrent cytogenetic abnormalities, association with unique gene expression and micro-RNA profiles and high stability at relapse, NPM1-mutated AML is regarded as a distinct genetic entity in the World Health Organization (WHO) classification of hematopoietic malignancies. Starting from the structure and functions of NPM1, we provide an overview of the potential targeted therapies against NPM1-mutated AML and discuss strategies aimed at interfering with the oligomerization (compound NSC348884) and the abnormal traffic of NPM1 (avrainvillamide, XPO1 inhibitors) as well as at inducing selective NPM1-mutant protein degradation (ATRA/ATO, deguelin, (-)-epigallocatechin-3-gallate, imidazoquinoxaline derivatives) and at targeting the integrity of nucleolar structure (actinomycin D). We also discuss the current therapeutic results obtained in NPM1-mutated AML with the BCL-2 inhibitor venetoclax and the preliminary clinical results using menin inhibitors targeting HOX/MEIS1 expression. Finally, we review various immunotherapeutic approaches in NPM1-mutated AML, including immune check-point inhibitors, CAR and TCR T-cell-based therapies against neoantigens created by the NPM1 mutations.

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Combinatorial treatment with menin and FLT3 inhibitors induces complete remission in AML models with activating FLT3 mutations

Cited by 30 publications

References 26 publications

Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia

Current status and future perspectives in targeted therapy of NPM1-mutated AML

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