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3.
Blood Cancer J ; 12(6): 95, 2022 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-35750691

RESUMO

Functional precision medicine in AML often relies on short-term in vitro drug sensitivity screening (DSS) of primary patient cells in standard culture conditions. We designed a niche-like DSS assay combining physiologic hypoxia (O2 3%) and mesenchymal stromal cell (MSC) co-culture with multiparameter flow cytometry to enumerate lymphocytes and differentiating (CD11/CD14/CD15+) or leukemic stem cell (LSC)-enriched (GPR56+) cells within the leukemic bulk. After functional validation of GPR56 expression as a surrogate for LSC enrichment, the assay identified three patterns of response, including cytotoxicity on blasts sparing LSCs, induction of differentiation, and selective impairment of LSCs. We refined our niche-like culture by including plasma-like amino-acid and cytokine concentrations identified by targeted metabolomics and proteomics of primary AML bone marrow plasma samples. Systematic interrogation revealed distinct contributions of each niche-like component to leukemic outgrowth and drug response. Short-term niche-like culture preserved clonal architecture and transcriptional states of primary leukemic cells. In a cohort of 45 AML samples enriched for NPM1c AML, the niche-like multiparametric assay could predict morphologically (p = 0.02) and molecular (NPM1c MRD, p = 0.04) response to anthracycline-cytarabine induction chemotherapy. In this cohort, a 23-drug screen nominated ruxolitinib as a sensitizer to anthracycline-cytarabine. This finding was validated in an NPM1c PDX model.


Assuntos
Leucemia Mieloide Aguda , Células-Tronco Mesenquimais , Antraciclinas/metabolismo , Antraciclinas/uso terapêutico , Citarabina/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Neoplásicas/metabolismo
4.
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
5.
Leukemia ; 35(3): 712-723, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32581253

RESUMO

Intra-tumor heterogeneity portends poor outcome in many cancers. In AML, a higher number of drivers worsens prognosis. The Shannon Index is a robust metric of clonal heterogeneity that accounts for the number of clones, but also their relative abundance. We show that a Shannon Index can be estimated from bulk sequencing, which is correlated (ρ = 0.76) with clonal diversity from single-colony genotyping. In a discovery cohort of 292 patients with sequencing of 43 genes, a higher number of drivers (HR = 1.18, P = 0.028) and a lower Shannon Index (HR = 0.68, P = 0.048), the latter reflecting clonal dominance, are independently associated with worse OS independently of European LeukemiaNet 2017 risk. These findings are validated in an independent cohort of 1184 patients with 111-gene sequencing (number of drivers HR = 1.16, P = 1 × 10-5, Shannon Index HR = 0.81, P = 0.007). By re-interrogating paired diagnosis/relapse exomes from 50 cytogenetically normal AMLs, we find clonal dominance at diagnosis to be correlated with the gain of a significantly higher number of mutations at relapse (P = 6 × 10-6), hence with clonal sweeping. Our results suggest that clonal dominance at diagnosis is associated with the presence of a leukemic phenotype allowing rapid expansion of new clones and driving relapse after chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Evolução Clonal , Regulação Neoplásica da Expressão Gênica , Leucemia Mieloide Aguda/patologia , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
6.
Cancer Discov ; 10(12): 1894-1911, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32826232

RESUMO

Deciphering the impact of metabolic intervention on response to anticancer therapy may elucidate a path toward improved clinical responses. Here, we identify amino acid-related pathways connected to the folate cycle whose activation predicts sensitivity to MYC-targeting therapies in acute myeloid leukemia (AML). We establish that folate restriction and deficiency of the rate-limiting folate cycle enzyme MTHFR, which exhibits reduced-function polymorphisms in about 10% of Caucasians, induce resistance to MYC targeting by BET and CDK7 inhibitors in cell lines, primary patient samples, and syngeneic mouse models of AML. Furthermore, this effect is abrogated by supplementation with the MTHFR enzymatic product CH3-THF. Mechanistically, folate cycle disturbance reduces H3K27/K9 histone methylation and activates a SPI1 transcriptional program counteracting the effect of BET inhibition. Our data provide a rationale for screening MTHFR polymorphisms and folate cycle status to nominate patients most likely to benefit from MYC-targeting therapies. SIGNIFICANCE: Although MYC-targeting therapies represent a promising strategy for cancer treatment, evidence of predictors of sensitivity to these agents is limited. We pinpoint that folate cycle disturbance and frequent polymorphisms associated with reduced MTHFR activity promote resistance to BET inhibitors. CH3-THF supplementation thus represents a low-risk intervention to enhance their effects.See related commentary by Marando and Huntly, p. 1791.This article is highlighted in the In This Issue feature, p. 1775.


Assuntos
Ácido Fólico/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Animais , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-myc/biossíntese , Células U937
7.
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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