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1.
Eur J Haematol ; 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32145118

RESUMO

INTRODUCTION: Clinical response and chemo-sensitivity of relapse or refractory AML patients were evaluated after rescue and bridge-to-transplant MEC regimen. METHODS AND PATIENTS: consecutive AML patients were treated with MEC from 2009 to 2018. Chemo-sensitivity was evaluated by WT1 quantification. RESULTS: 27/55 patients (49.1%) had AML resistant to induction and 28/55 patients (50.9%) had AML relapse. 25/55 patients (45.5%) achieved a CR after one course of MEC; 12 patients (21.8%) achieved WT1 negativity. In 12 patients, a second MEC was administered. 4 out of 12 patients improved significantly their response with the 2nd MEC. MEC was an effective bridge to transplant, 32/55 patients (58.2%), received an allogenic stem cell transplant. Median overall survival (OS) from MEC was 455 days (95% C.I. 307-602 days.); Patient with WT1 negative CR had the best OS (p<.000) CONCLUSION: WT1 is a useful marker of chemo-sensitivity after MEC as rescue and bridge-to-transplant therapy.

2.
Mol Genet Genomics ; 295(1): 107-120, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31506717

RESUMO

The oriental gall wasp Dryocosmus kuriphilus represents a limiting pest for the European Chestnut (Castanea sativa, Fagaceae) as it creates severe yield losses. The European Chestnut is a deciduous tree, having major social, economic and environmental importance in Southern Europe, covering an area of 2.53 million hectares, including 75,000 ha devoted to fruit production. Cultivars show different susceptibility and very few are resistant to gall wasp. To deeply investigate the plant response and understand which factors can lead the plant to develop or not the gall, the study of transcriptome is basic (fundamental). To date, little transcriptomic information are available for C. sativa species. Hence, we present a de novo assembly of the chestnut transcriptome of the resistant Euro-Japanese hybrid 'Bouche de Bétizac' (BB) and the susceptible cultivar 'Madonna' (M), collecting RNA from buds at different stages of budburst. The two transcriptomes were assembled into 34,081 (BB) and 30,605 (M) unigenes, respectively. The former was used as a reference sequence for further characterization analyses, highlighting the presence of 1444 putative resistance gene analogs (RGAs) and about 1135 unigenes, as putative MiRNA targets. A global quantitative transcriptome profiling comparing the resistant and the susceptible cultivars, in the presence or not of the gall wasp, revealed some GO enrichments as "response to stimulus" (GO:0050896), and "developmental processes" (e.g., post-embryonic development, GO:0009791). Many up-regulated genes appeared to be transcription factors (e.g., RAV1, AP2/ERF, WRKY33) or protein regulators (e.g., RAPTOR1B) and storage proteins (e.g., LEA D29) involved in "post-embryonic development". Our analysis was able to provide a large amount of information, including 7k simple sequence repeat (SSR) and 335k single-nucleotide polymorphism (SNP)/INDEL markers, and generated the first reference unigene catalog for the European Chestnut. The transcriptome data for C. sativa will contribute to understand the genetic basis of the resistance to gall wasp and will provide useful information for next molecular genetic studies of this species and its relatives.


Assuntos
Fagaceae/genética , Transcriptoma/genética , Vespas/patogenicidade , Animais , Europa (Continente) , Fagaceae/parasitologia , Perfilação da Expressão Gênica/métodos , Repetições de Microssatélites/genética , Anotação de Sequência Molecular/métodos , Doenças das Plantas/parasitologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição/genética , Árvores/genética , Árvores/parasitologia , Regulação para Cima/genética
3.
J Oncol ; 2019: 5985923, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827512

RESUMO

Somatic mutations of DNMT3A occur in about 20% of acute myeloid leukemia (AML) patients. They mostly consist in heterozygous missense mutations targeting a hotspot site at R882 codon, which exhibit a dominant negative effect and are associated with high myeloblast count, advanced age, and poor prognosis. Other types of mutations such as truncations, insertions, or single-nucleotide deletion also affect the DNMT3A gene, though with lower frequency. The present study aimed to characterize two DNMT3A gene mutations identified by next-generation sequencing (NGS), through analysis of protein stability and DNA methylation status at CpG islands. The first mutation was a single-nucleotide variant of DNMT3A at exon 20 causing a premature STOP codon (c.2385G > A; p.Trp795 ∗ ; NM_022552.4). The DNMT3A mutation load increased from 4.5% to 38.2% during guadecitabine treatment, with a dominant negative effect on CpG methylation and on protein expression. The second mutation was a novel insertion of 35 nucleotides in exon 22 of DNMT3A (NM_022552.4) that introduced a STOP codon too, after the amino acid Glu863 caused by a frameshift insertion (c.2586_2587insTCATGAATGAGAAAGAGGACATCTTATGGTGCACT; p. Thr862_Glu863fsins). The mutation, which was associated with reduced DNMT3A expression and CpG methylation, persisted at relapse with minor changes in the methylation profile and at protein level. Our data highlight the need to better understand the consequences of DNMT3A mutations other than R882 substitutions in the leukemogenic process in order to tailor patient treatments, thus avoiding therapeutic resistance and disease relapse.

4.
Cancers (Basel) ; 11(11)2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31717700

RESUMO

INTRODUCTION: Screening for synthetic lethality markers has demonstrated that the inhibition of the cell cycle checkpoint kinases WEE1 together with CHK1 drastically affects stability of the cell cycle and induces cell death in rapidly proliferating cells. Exploiting this finding for a possible therapeutic approach has showed efficacy in various solid and hematologic tumors, though not specifically tested in acute lymphoblastic leukemia. METHODS: The efficacy of the combination between WEE1 and CHK1 inhibitors in B and T cell precursor acute lymphoblastic leukemia (B/T-ALL) was evaluated in vitro and ex vivo studies. The efficacy of the therapeutic strategy was tested in terms of cytotoxicity, induction of apoptosis, and changes in cell cycle profile and protein expression using B/T-ALL cell lines. In addition, the efficacy of the drug combination was studied in primary B-ALL blasts using clonogenic assays. RESULTS: This study reports, for the first time, the efficacy of the concomitant inhibition of CHK1/CHK2 and WEE1 in ALL cell lines and primary leukemic B-ALL cells using two selective inhibitors: PF-0047736 (CHK1/CHK2 inhibitor) and AZD-1775 (WEE1 inhibitor). We showed strong synergism in the reduction of cell viability, proliferation and induction of apoptosis. The efficacy of the combination was related to the induction of early S-phase arrest and to the induction of DNA damage, ultimately triggering cell death. We reported evidence that the efficacy of the combination treatment is independent from the activation of the p53-p21 pathway. Moreover, gene expression analysis on B-ALL primary samples showed that Chek1 and Wee1 are significantly co-expressed in samples at diagnosis (Pearson r = 0.5770, p = 0.0001) and relapse (Pearson r= 0.8919; p = 0.0001). Finally, the efficacy of the combination was confirmed by the reduction in clonogenic survival of primary leukemic B-ALL cells. CONCLUSION: Our findings suggest that the combination of CHK1 and WEE1 inhibitors may be a promising therapeutic strategy to be tested in clinical trials for adult ALL.

5.
Int J Mol Sci ; 20(11)2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31163594

RESUMO

Acute Myeloid Leukemia (AML) is an extremely heterogeneous group of hematological neoplasms, for which allogeneic stem cell transplantation (HSCT) still represents the only potentially curative option in the majority of cases. However, elderly age and clinically severe comorbidities may often exclude a wide amount of patients from this therapeutic approach, underlying the urgent need for alternative strategies. Thanks to the introduction of advanced high-throughput techniques, light is being shed on the pathogenesis of AML, identifying molecular recurrent mutations as responsible for the onset, as well as progression, of disease. As a consequence, and in parallel, many new compounds, including targeted therapies (FMS-like tyrosine kinase 3 (FLT3) and Isocitrate dehydrogenase 1-2 (IDH1-2) inhibitors), have found a wide room of application in this setting, and are now available in daily practice, or in late phases of clinical development. Moreover, several further innovative molecules are currently under investigation, and promising results for many of them have already been reported. In this review, we will present an update on the most relevant molecular alterations of AML, focusing on the most frequent genomic mutations of the disease, for which compounds have been approved or are still currently under investigation.


Assuntos
Biomarcadores Tumorais , Leucemia Mieloide Aguda/genética , Mutação , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Frequência do Gene , Predisposição Genética para Doença , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento
6.
Gastroenterology ; 157(3): 807-822, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31194980

RESUMO

BACKGROUND & AIMS: In one-third of hepatocellular carcinomas (HCCs), cancer cells have mutations that activate ß-catenin pathway. These cells have alterations in glutamine, bile, and lipid metabolism. We investigated whether positron emission tomography (PET) imaging allows identification of altered metabolic pathways that might be targeted therapeutically. METHODS: We studied mice with activation of ß-catenin in liver (Apcko-liv mice) and male C57Bl/6 mice given injections of diethylnitrosamine, which each develop HCCs. Mice were fed a conventional or a methionine- and choline-deficient diet or a choline-deficient (CD) diet. Choline uptake and metabolism in HCCs were analyzed by micro-PET imaging of mice; livers were collected and analyzed by histologic, metabolomic, messenger RNA quantification, and RNA-sequencing analyses. Fifty-two patients with HCC underwent PET imaging with 18F-fluorodeoxyglucose, followed by 18F-fluorocholine tracer metabolites. Human HCC specimens were analyzed by immunohistochemistry, quantitative polymerase chain reaction, and DNA sequencing. We used hepatocytes and mouse tumor explants for studies of incorporation of radiolabeled choline into phospholipids and its contribution to DNA methylation. We analyzed HCC progression in mice fed a CD diet. RESULTS: Livers and tumors from Apcko-liv mice had increased uptake of dietary choline, which contributes to phospholipid formation and DNA methylation in hepatocytes. In patients and in mice, HCCs with activated ß-catenin were positive in 18F-fluorocholine PET, but not 18F-fluorodeoxyglucose PET, and they overexpressed the choline transporter organic cation transporter 3. The HCC cells from Apcko-liv mice incorporated radiolabeled methyl groups of choline into phospholipids and DNA. In Apcko-liv mice, the methionine- and choline-deficient diet reduced proliferation and DNA hypermethylation of hepatocytes and HCC cells, and the CD diet reduced long-term progression of tumors. CONCLUSIONS: In mice and humans, HCCs with mutations that activate ß-catenin are characterized by increased uptake of a fluorocholine tracer, but not 18F-fluorodeoxyglucose, revealed by PET. The increased uptake of choline by HCCs promotes phospholipid formation, DNA hypermethylation, and hepatocyte proliferation. In mice, the CD diet reverses these effects and promotes regression of HCCs that overexpress ß-catenin.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/genética , Mutação , Tomografia por Emissão de Pósitrons , beta Catenina/genética , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Proliferação de Células , Colina/administração & dosagem , Colina/análogos & derivados , Deficiência de Colina/complicações , Metilação de DNA , Dietilnitrosamina , Modelos Animais de Doenças , Genes APC , Predisposição Genética para Doença , Humanos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Masculino , Metionina/deficiência , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Fosfolipídeos/metabolismo , Valor Preditivo dos Testes , Compostos Radiofarmacêuticos/administração & dosagem , beta Catenina/metabolismo
7.
Liver Int ; 39(4): 727-739, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30721564

RESUMO

BACKGROUND & AIMS: Loss of hepatocyte nuclear factor-4α (HNF4α), a critical factor driving liver development and differentiation, is frequently associated with hepatocellular carcinoma (HCC). Our recent data revealed that HNF4α level was decreased in mouse and human HCCs with activated ß-catenin signalling. In addition, increasing HNF4α level by miR-34a inhibition slowed tumour progression of ß-catenin-activated HCC in mice. METHODS: We generated a Hnf4aflox/flox/ Apcflox/flox /TTR-CreERT 2 (Hnf4a/Apc∆Hep ) mouse line and evaluated the impact of Hnf4a disruption on HCC development and liver homoeostasis. RESULTS: There was no significant impact of Hnf4a disruption on tumour onset and progression in Apc∆Hep model. However, we observed an unexpected phenotype in 28% of Hnf4a∆Hep mice maintained in a conventional animal facility, which presented disorganized portal triads, characterized by stenosis of the portal vein and increased number and size of hepatic arteries and bile ducts. These abnormal portal structures resemble the human idiopathic non-cirrhotic portal hypertension syndrome. We correlated the presence of portal remodelling with a higher expression of protein and mRNA levels of TGFß and BMP7, a key regulator of the TGFß-dependent endothelial-to-mesenchymal transition. CONCLUSION: These data demonstrate that HNF4α does not play a major role during ß-catenin-driven HCC, thus revealing that the tumour suppressor role of HNF4α is far more complex and dependent probably on its temporal expression and tumour context. However, HNF4α loss in adult hepatocytes could induce abnormal portal structures resembling the human idiopathic non-cirrhotic portal hypertension syndrome, which may result from endothelial- and epithelial-to-mesenchymal transitions.

8.
Gut ; 68(2): 322-334, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29650531

RESUMO

OBJECTIVES: CTNNB1-mutated hepatocellular carcinomas (HCCs) constitute a major part of human HCC and are largely inaccessible to target therapy. Yet, little is known about the metabolic reprogramming induced by ß-catenin oncogenic activation in the liver. We aimed to decipher such reprogramming and assess whether it may represent a new avenue for targeted therapy of CTNNB1-mutated HCC. DESIGN: We used mice with hepatocyte-specific oncogenic activation of ß-catenin to evaluate metabolic reprogramming using metabolic fluxes on tumourous explants and primary hepatocytes. We assess the role of Pparα in knock-out mice and analysed the consequences of fatty acid oxidation (FAO) using etomoxir. We explored the expression of the FAO pathway in an annotated human HCC dataset. RESULTS: ß-catenin-activated HCC were not glycolytic but intensively oxidised fatty acids. We found that Pparα is a ß-catenin target involved in FAO metabolic reprograming. Deletion of Pparα was sufficient to block the initiation and progression of ß-catenin-dependent HCC development. FAO was also enriched in human CTNNB1-mutated HCC, under the control of the transcription factor PPARα. CONCLUSIONS: FAO induced by ß-catenin oncogenic activation in the liver is the driving force of the ß-catenin-induced HCC. Inhibiting FAO by genetic and pharmacological approaches blocks HCC development, showing that inhibition of FAO is a suitable therapeutic approach for CTNNB1-mutated HCC.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Ácidos Graxos/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , beta Catenina/metabolismo , Animais , Compostos de Epóxi/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Knockout , Mutação , Oxirredução , PPAR alfa/fisiologia , beta Catenina/genética
9.
BMC Cancer ; 18(1): 1117, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30442119

RESUMO

BACKGROUND: Extramedullary involvement of B-cell Acute Lymphoblastic Leukemia (EM-ALL) is a rare occurrence, characterized by dismal outcome and the absence of a defined and shared therapeutic approach. In the landscape of innovative compounds, inotuzumab ozogamicin (IO) is a promising drug, whose mechanism of action relies on the killing of CD22 positive leukemic cells, through the delivery, after cell binding, of a molecule of calicheamicin. CASE PRESENTATION: We report two cases of CD22 positive relapsed EM-ALL treated with IO, obtained as compassionate use. Case 1, a 66 years old woman, affected by Philadelphia (Ph) negative B-ALL, relapsed with extramedullary involvement after 6 standard chemotherapy courses, who reached a complete metabolic response with IO treatment. Case 2, a 67 years old man with Ph positive B-ALL, initially treated with ponatinib, a third generation tyrosine-kinase inhibitor (TKI), obtaining a prolonged deep molecular remission. Nevertheless, for skin relapse during TKI treatment, the patient received local radiotherapy and, shortly after, standard chemotherapy, as multiple abdominal sites of relapse were detected too, with no response. The patient then received IO, obtained as compassionate use, with a good metabolic response. CONCLUSIONS: These two cases suggest a possible key role of IO in the setting of advanced CD22 positive ALL, and underline its potential activity also in patients with EM involvement, relapsed after or refractory to conventional chemotherapy. Despite the well known hepatotoxic effect of the compound (Sinusoid Occlusive Syndrome), neither of them had such adverse event, moreover the second patient safely underwent allogeneic bone marrow transplantation.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/antagonistas & inibidores , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Masculino , Recidiva Local de Neoplasia/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Resultado do Tratamento
10.
J Hematol Oncol ; 11(1): 99, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30068368

RESUMO

BACKGROUND: Despite the recent progress that has been made in the understanding and treatment of acute lymphoblastic leukemia (ALL), the outcome is still dismal in adult ALL cases. Several studies in solid tumors identified high expression of WEE1 kinase as a poor prognostic factor and reported its role as a cancer-conserving oncogene that protects cancer cells from DNA damage. Therefore, the targeted inhibition of WEE1 kinase has emerged as a rational strategy to sensitize cancer cells to antineoplastic compounds, which we evaluate in this study. METHODS: The effectiveness of the selective WEE1 inhibitor AZD-1775 as a single agent and in combination with different antineoplastic agents in B and T cell precursor ALL (B/T-ALL) was evaluated in vitro and ex vivo studies. The efficacy of the compound in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed using different B/T-ALL cell lines and confirmed in primary ALL blasts. RESULTS: We showed that WEE1 was highly expressed in adult primary ALL bone marrow and peripheral blood blasts (n = 58) compared to normal mononuclear cells isolated from the peripheral blood of healthy donors (p = 0.004). Thus, we hypothesized that WEE1 could be a rational target in ALL, and its inhibition could enhance the cytotoxicity of conventional therapies used for ALL. We evaluated the efficacy of AZD-1775 as a single agent and in combination with several antineoplastic agents, and we elucidated its mechanisms of action. AZD-1775 reduced cell viability in B/T-ALL cell lines by disrupting the G2/M checkpoint and inducing apoptosis. These findings were confirmed in human primary ALL bone marrow and peripheral blood blasts (n = 15). In both cell lines and primary leukemic cells, AZD-1775 significantly enhanced the efficacy of several tyrosine kinase inhibitors (TKIs) such as bosutinib, imatinib, and ponatinib, and of chemotherapeutic agents (clofarabine and doxorubicin) in terms of the reduction of cell viability, apoptosis induction, and inhibition of proliferation. CONCLUSIONS: Our data suggest that WEE1 plays a role in ALL blast's survival and is a bona fide target for therapeutic intervention. These data support the evaluation of the therapeutic potential of AZD-1775 as chemo-sensitizer agent for the treatment of B/T-ALL.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Nucleares/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Tirosina Quinases/genética , Linhagem Celular Tumoral , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo
11.
BMC Cancer ; 17(1): 523, 2017 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-28779753

RESUMO

BACKGROUND: The treatment of Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL) patients who harbor the T315I BCR-ABL1 mutation or who have two or more mutations in the same BCR-ABL1 molecule is particularly challenging since first and second-generation Tyrosine Kinase Inhibitors (TKIs) are ineffective. Ponatinib, blinatumomab, chemotherapy and transplant are the currently available options in these cases. CASE PRESENTATION: We here report the case of a young Ph+ ALL patient who relapsed on front-line dasatinib therapy because of two independent T315I-positive subclones, resulting from different nucleotide substitutions -one of whom never reported previously- and where additional mutant clones outgrew and persisted despite ponatinib, transplant, blinatumomab and conventional chemotherapy. Deep Sequencing (DS) was used to dissect the complexity of BCR-ABL1 kinase domain (KD) mutation status and follow the kinetics of different mutant clones across the sequential therapeutic approaches. CONCLUSIONS: This case presents several peculiar and remarkable aspects: i) distinct clones may acquire the same amino acid substitution via different nucleotide changes; ii) the T315I mutation may arise also from an 'act' to 'atc' codon change; iii) the strategy of temporarily replacing TKI therapy with chemo or immunotherapy, in order to remove the selective pressure and deselect aggressive mutant clones, cannot always be expected to be effective; iv) BCR-ABL1-mutated sub-clones may persist at very low levels (undetectable even by Deep Sequencing) for long time and then outcompete BCR-ABL1-unmutated ones becoming dominant even in the absence of any TKI selective pressure.


Assuntos
Evolução Clonal/genética , Proteínas de Fusão bcr-abl/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adulto , Substituição de Aminoácidos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Humanos , Imunofenotipagem , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Análise de Sequência de DNA , Transcrição Genética , Falha de Tratamento , Resultado do Tratamento , Adulto Jovem
12.
Expert Opin Pharmacother ; 17(18): 2479-2486, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27829292

RESUMO

INTRODUCTION: Therapy for acute myeloid leukemia (AML) in elderly populations (>65 years) is still a challenge for scientists and hematologists worldwide, and represents an urgent medical need. Notably, the identification and the recognition of molecular and epigenetic mechanisms involved in the pathogenesis of such a heterogeneous disease, are providing new tools for a more successful and 'targeted' approach. Azacitidine is a hypomethylating agent (HMA) with relevant activity in patients affected by myelodysplastic syndrome (MDS) and AML with low blast cells percentage (>30%), in terms of reduction of transfusion dependence, and improvement of quality of life. Areas covered: This review summarizes the mechanism of action, safety profile and efficacy of azacitidine in the field of elderly AML populations, providing up-to-date references on this subset of high-risk patients. Expert opinion: HMAs are the first successful treatment for elderly patients with high-risk MDS and are effective for some AML subtypes. Translational studies based on gene expression profiling and molecular sequencing, would be able to identify, in the near future, patients with a favorable profile of response to these compounds suggesting new potential treatment combinations also.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/farmacologia , Azacitidina/farmacologia , Ensaios Clínicos como Assunto/métodos , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/tratamento farmacológico , Qualidade de Vida , Resultado do Tratamento
13.
Oncotarget ; 7(33): 53377-53391, 2016 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-27438145

RESUMO

During the last few years many Checkpoint kinase 1/2 (Chk1/Chk2) inhibitors have been developed for the treatment of different type of cancers. In this study we evaluated the efficacy of the Chk 1/2 inhibitor prexasertib mesylate monohydrate in B-/T- cell progenitor acute lymphoblastic leukemia (ALL) as single agent and in combination with other drugs. The prexasertib reduced the cell viability in a dose and time dependent manner in all the treated cell lines. The cytotoxic activity was confirmed by the increment of apoptotic cells (Annexin V/Propidium Iodide staining), by the increase of γH2A.X protein expression and by the activation of different apoptotic markers (Parp-1 and pro-Caspase3 cleavage). Furthermore, the inhibition of Chk1 changed the cell cycle profile. In order to evaluate the chemo-sensitizer activity of the compound, different cell lines were treated for 24 and 48 hours with prexasertib in combination with other drugs (imatinib, dasatinib and clofarabine). The results from cell line models were strengthened in primary leukemic blasts isolated from peripheral blood of adult acute lymphoblastic leukemia patients. In this study we highlighted the mechanism of action and the effectiveness of prexasertib as single agent or in combination with other conventional drugs like imatinib, dasatinib and clofarabine in the treatment of B-/T-ALL.


Assuntos
Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Quinase do Ponto de Checagem 2/antagonistas & inibidores , Pirazinas/farmacologia , Pirazóis/farmacologia , Nucleotídeos de Adenina/farmacologia , Antineoplásicos/farmacologia , Arabinonucleosídeos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quinase 1 do Ponto de Checagem/metabolismo , Quinase do Ponto de Checagem 2/metabolismo , Clofarabina , Dasatinibe/farmacologia , Sinergismo Farmacológico , Humanos , Mesilato de Imatinib/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Inibidores de Proteínas Quinases/farmacologia
14.
Gut ; 65(6): 1024-34, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-25792709

RESUMO

OBJECTIVE: Hepatocellular carcinoma (HCC) is the most prevalent primary tumour of the liver. About a third of these tumours presents activating mutations of the ß-catenin gene. The molecular pathogenesis of HCC has been elucidated, but mortality remains high, and new therapeutic approaches, including treatments based on microRNAs, are required. We aimed to identify candidate microRNAs, regulated by ß-catenin, potentially involved in liver tumorigenesis. DESIGN: We used a mouse model, in which ß-catenin signalling was overactivated exclusively in the liver by the tamoxifen-inducible and Cre-Lox-mediated inactivation of the Apc gene. This model develops tumours with properties similar to human HCC. RESULTS: We found that miR-34a was regulated by ß-catenin, and significantly induced by the overactivation of ß-catenin signalling in mouse tumours and in patients with HCC. An inhibitor of miR-34a (locked nucleic acid, LNA-34a) exerted antiproliferative activity in primary cultures of hepatocyte. This inhibition of proliferation was associated with a decrease in cyclin D1 levels, orchestrated principally by HNF-4α, a target of miR-34a considered to act as a tumour suppressor in the liver. In vivo, LNA-34a approximately halved progression rates for tumours displaying ß-catenin activation together with an activation of caspases 2 and 3. CONCLUSIONS: This work demonstrates the key oncogenic role of miR-34a in liver tumours with ß-catenin gene mutations. We suggest that patients diagnosed with HCC with ß-catenin mutations could be treated with an inhibitor of miR-34a. The potential value of this strategy lies in the modulation of the tumour suppressor HNF-4α, which targets cyclin D1, and the induction of a proapoptotic programme.


Assuntos
Ciclina D1/genética , Neoplasias Hepáticas Experimentais/genética , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Mutação , beta Catenina/genética , Animais , Carcinoma Hepatocelular/terapia , Humanos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas Experimentais/terapia , Camundongos
15.
Oncotarget ; 6(31): 31284-94, 2015 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-26384303

RESUMO

FLT3 internal tandem duplication (ITD), one of the most frequent mutations in Acute Myeloid Leukemia (AML), is reported to be an unstable marker, as it can evolve from FLT3 ITD- to ITD+ during the disease course. A single-gene sensitive mutational screening approach may be helpful for better clarifying the exact timing of mutation occurrence, especially when FLT3 ITD appears to occur late, at disease progression. We developed an amplicon-based ultra-deep-sequencing (UDS) approach for FLT3 mutational screening. We exploited this highly sensitive technology for the retrospective screening of diagnosis, relapse and follow-up samples of 5 out of 256 cytogenetically normal (CN-) AML who were FLT3 wild-type at presentation, but tested ITD+ at relapse or disease progression. Our study revealed that all patients carried a small ITD+ clone at diagnosis, which was undetectable by routine analysis (0,2-2% abundance). The dynamics of ITD+ clones from diagnosis to disease progression, assessed by UDS, reflected clonal evolution under treatment pressure. UDS appears as a valuable tool for FLT3 mutational screening and for the assessment of minimal residual disease (MRD) during follow-up, by detecting small ITD+ clones that may survive chemotherapy, evolve over time and definitely worsen the prognosis of CN-AML patients.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia Mieloide Aguda/diagnóstico , Mutação/genética , Neoplasia Residual/diagnóstico , Sequências de Repetição em Tandem/genética , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , Idoso , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasia Residual/genética , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
16.
Hematol Rep ; 6(3): 5554, 2014 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-25317319

RESUMO

In the last two decades great improvements have been made in the treatment of childhood acute lymphoblastic leukemia, with 5-year overall survival rates currently approaching almost 90%. In comparison, results reported in adolescents and young adults (AYAs) are relatively poor. In adults, results have improved, but are still lagging behind those obtained in children. Possible reasons for this different pattern of results include an increased incidence of unfavorable and a decreased incidence of favorable cytogenetic abnormalities in AYAs compared with children. Furthermore, in AYAs less intensive treatments (especially lower cumulative doses of drugs such as asparaginase, corticosteroids and methotrexate) and longer gaps between courses of chemotherapy are planned compared to those in children. However, although favorable results obtained in AYAs receiving pediatric protocols have been consistently reported in several international collaborative trials, physicians must also be aware of the specific toxicity pattern associated with increased success in AYAs, since an excess of toxicity may compromise overall treatment schedule intensity. Cooperative efforts between pediatric and adult hematologists in designing specific protocols for AYAs are warranted.

17.
Hematol Rep ; 6(3): 5565, 2014 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-25317320

RESUMO

We report here the case of a young adult affected by pre B-cell acute lymphoblastic leukemia (ALL), who developed, during a pediatric-like chemotherapy consolidation schedule with high dosage of Methotrexate, a severe neurological toxicity. Clinical presentation and neuroimaging data were diagnostic for posterior reversible encephalopathy syndrome (PRES). A complete resolution was quickly obtained with medical blood pressure control and anticonvulsants administration. To the best of our knowledge, this is the first case of PRES described in the adult ALL setting. Currently, the clinical management of this aggressive disease is moving towards a pediatric-like approach also in adult patients, due to the better outcome reached with intensive chemotherapeutic regimens in children population. However, therapy-related toxicities have to be taken into account, since their onset may adversely affect patients' clinical outcome.

18.
Recenti Prog Med ; 105(3): 118-22, 2014 Mar.
Artigo em Italiano | MEDLINE | ID: mdl-24675454

RESUMO

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders of the myeloid lineage characterized by peripheral cytopenias and frequent leukemic evolution. MDS differ for clinical presentation, disease behavior and progression and this is the reflection of remarkable variability at molecular level. To this moment disease diagnosis is still dependent on bone marrow morphology that, although high concordance rates among experts are reported, remains subjective. Karyotype analysis is mandatory but diagnosis may be difficult in presence of normal karyotype or non-informative cytogenetics. Standardized molecular markers are needed to better define diagnosis, prediction of disease progression and prognosis. Furthermore, a molecular biology analysis could provide an important therapeutic tool towards tailored therapy and new insights in the disease's biology.


Assuntos
Leucemia Mieloide Aguda/diagnóstico , Biologia Molecular/métodos , Síndromes Mielodisplásicas/diagnóstico , Biomarcadores/metabolismo , Medula Óssea/patologia , Análise Citogenética , Progressão da Doença , Humanos , Cariotipagem/métodos , Leucemia Mieloide Aguda/patologia , Síndromes Mielodisplásicas/patologia , Prognóstico
19.
Hepatology ; 59(6): 2344-57, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24214913

RESUMO

UNLABELLED: ß-catenin signaling can be both a physiological and oncogenic pathway in the liver. It controls compartmentalized gene expression, allowing the liver to ensure its essential metabolic function. It is activated by mutations in 20%-40% of hepatocellular carcinomas (HCCs) with specific metabolic features. We decipher the molecular determinants of ß-catenin-dependent zonal transcription using mice with ß-catenin-activated or -inactivated hepatocytes, characterizing in vivo their chromatin occupancy by T-cell factor (Tcf)-4 and ß-catenin, transcriptome, and metabolome. We find that Tcf-4 DNA bindings depend on ß-catenin. Tcf-4/ß-catenin binds Wnt-responsive elements preferentially around ß-catenin-induced genes. In contrast, genes repressed by ß-catenin bind Tcf-4 on hepatocyte nuclear factor 4 (Hnf-4)-responsive elements. ß-Catenin, Tcf-4, and Hnf-4α interact, dictating ß-catenin transcription, which is antagonistic to that elicited by Hnf-4α. Finally, we find the drug/bile metabolism pathway to be the one most heavily targeted by ß-catenin, partly through xenobiotic nuclear receptors. CONCLUSIONS: ß-catenin patterns the zonal liver together with Tcf-4, Hnf-4α, and xenobiotic nuclear receptors. This network represses lipid metabolism and exacerbates glutamine, drug, and bile metabolism, mirroring HCCs with ß-catenin mutational activation.


Assuntos
Fator 4 Nuclear de Hepatócito/metabolismo , Hepatócitos/metabolismo , Neoplasias Hepáticas/etiologia , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , beta Catenina/metabolismo , Animais , Cromatina/metabolismo , Redes Reguladoras de Genes , Humanos , Metabolismo dos Lipídeos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Receptor Cross-Talk , beta Catenina/genética
20.
Hematol Rep ; 5(2): 26-7, 2013 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-23888243

RESUMO

We report a case of a patient affected by juvenile polyposis and hereditary hemorrhagic telangiectasia linked to a SMAD4 mutation who developed acute lymphoblastic leukemia positive for the Philadelphia chromosome translocation and with a complex karyotype. During the treatment with the tyrosine kinase inhibitor dasatinib the patient presented recurrent severe gastrointestinal hemorrhages linked to the genetic background and aggravated by thrombocytopenia.

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