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1.
Leukemia ; 36(6): 1585-1595, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35474100

RESUMO

By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11 impaired the viability and clonogenic capacity of AML cell lines in a cysteine-dependent manner. Sulfasalazine, a broadly available drug with xCT inhibitory activity, had anti-leukemic activity against primary AML samples in ex vivo cultures. Multiple metabolic pathways were impacted upon xCT inhibition, resulting in depletion of glutathione pools in leukemic cells and oxidative stress-dependent cell death, only in part through ferroptosis. Higher expression of cysteine metabolism genes and greater cystine dependency was noted in NPM1-mutated AMLs. Among eight anti-leukemic drugs, the anthracycline daunorubicin was identified as the top synergistic agent in combination with sulfasalazine in vitro. Addition of sulfasalazine at a clinically relevant concentration significantly augmented the anti-leukemic activity of a daunorubicin-cytarabine combination in a panel of 45 primary samples enriched in NPM1-mutated AML. These results were confirmed in vivo in a patient-derived xenograft model. Collectively, our results nominate cystine import as a druggable target in AML and raise the possibility to repurpose sulfasalazine for the treatment of AML, notably in combination with chemotherapy.


Assuntos
Cistina , Leucemia Mieloide Aguda , Linhagem Celular Tumoral , Cisteína , Cistina/metabolismo , Cistina/uso terapêutico , Daunorrubicina/farmacologia , Daunorrubicina/uso terapêutico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Proteínas Nucleares , Sulfassalazina/farmacologia , Sulfassalazina/uso terapêutico
2.
Leuk Res ; 87: 106269, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31751766

RESUMO

Bromodomain and Extra-Terminal inhibitors (BETi) such as OTX015 are active in Acute Myeloid Leukaemias (AML). Their activity on Leukemic Stem Cells (LSCs) is less documented. We interrogated the anti-LSC activity of OTX015 in a niche-like long-term culture in 26 primary AML samples and validated our findings in vivo. OTX015 impaired LSCs in AMLs harbouring Core Binding Factor or KMT2A gene fusions, NPM1 or chromatin/spliceosome genes mutations, but not in those with aneuploidy/TP53 mutations. In four patients, we dissected the transcriptomic footprint of Bet inhibition on LSCs versus blasts. Our results can instruct future clinical trials of BETi in AML.


Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteínas/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/terapia , Camundongos , Camundongos Transgênicos , Mutação , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/fisiologia , Nucleofosmina , Oncogenes/genética , Proteínas/genética , Resultado do Tratamento , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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