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1.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070902

RESUMO

FLT3-mutated acute myeloid leukemia accounts for around 30% of acute myeloid leukemia (AML). The mutation carried a poor prognosis until the rise of tyrosine kinase inhibitors (TKIs). New potent and specific inhibitors have successfully altered the course of the disease, increasing the complete response rate and the survival of patients with FLT3-mutated AML. The aim of this article is to review all the current knowledge on these game-changing drugs as well as the unsolved issues raised by their use for fit and unfit FLT3-mutated AML patients. To this end, we analyzed the results of phase I, II, III clinical trials evaluating FLT3-TKI both in the first-line, relapse monotherapy or in combination referenced in the PubMed, the American Society of Hematology, the European Hematology Association, and the Clinicaltrials.gov databases, as well as basic science reports on TKI resistance from the same databases. The review follows a chronological presentation of the different trials that allowed the development of first- and second-generation TKI and ends with a review of the current lines of evidence on leukemic blasts resistance mechanisms that allow them to escape TKI.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Mieloide Aguda/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genética , Ensaios Clínicos como Assunto , Bases de Dados Factuais , Expressão Gênica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Mutação , Recidiva , Transplante de Células-Tronco/métodos , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/metabolismo
2.
Blood Cancer J ; 11(6): 115, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135309
3.
Lancet Haematol ; 8(7): e481-e491, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34171279

RESUMO

BACKGROUND: Daunorubicin and cytarabine are used as standard induction chemotherapy for patients with acute myeloid leukaemia. CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. Primary analysis of the phase 3 trial in adults aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia provided support for approval of CPX-351 by the US Food and Drug Administration and European Medicines Agency. We describe the prospectively planned final 5-year follow-up results. METHODS: This randomised, open-label, multicentre, phase 3 trial was done across 39 academic and regional cancer centres in the USA and Canada. Eligible patients were aged 60-75 years and had a pathological diagnosis of acute myeloid leukaemia according to WHO 2008 criteria, no previous induction therapy for acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned 1:1 (stratified by age and acute myeloid leukaemia subtype) to receive up to two induction cycles of CPX-351 (100 units/m2 administered as a 90-min intravenous infusion on days 1, 3, and 5; on days 1 and 3 for the second induction) or standard chemotherapy (cytarabine 100 mg/m2 per day continuous intravenous infusion for 7 days plus intravenous daunorubicin 60 mg/m2 on days 1, 2, and 3 [7+3]; cytarabine for 5 days and daunorubicin on days 1 and 2 for the second induction [5+2]). Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery could receive up to tw cycles of consolidation therapy with CPX-351 (65 units/m2 90-min infusion on days 1 and 3) or chemotherapy (5+2, same dosage as in the second induction cycle). The primary outcome was overall survival analysed in all randomly assigned patients. No additional adverse events were collected with long-term follow-up, except data for deaths. This trial is registered with ClinicalTrials.gov, NCT01696084, and is complete. FINDINGS: Between Dec 20, 2012, and Nov 11, 2014, 309 patients with newly diagnosed high-risk or secondary acute myeloid leukaemia were enrolled and randomly assigned to receive CPX-351 (153 patients) or 7+3 (156 patients). At a median follow-up of 60·91 months (IQR 60·06-62·98) in the CPX-351 group and 59·93 months (59·73-60·50) in the 7+3 group, median overall survival was 9·33 months (95% CI 6·37-11·86) with CPX-351 and 5·95 months (4·99-7·75) with 7+3 (HR 0·70, 95% CI 0·55-0·91). 5-year overall survival was 18% (95% CI 12-25%) in the CPX-351 group and 8% (4-13%) in the 7+3 group. The most common cause of death in both groups was progressive leukaemia (70 [56%] of 124 deaths in the CPX-351 group and 74 [53%] of 140 deaths in the 7+3 group). Six (5%) of 124 deaths in the CPX-351 group and seven (5%) of 140 deaths in the 7+3 group were considered related to study treatment. INTERPRETATION: After 5 years of follow-up, the improved overall survival with CPX-351 versus 7+3 was maintained, which supports the previous evidence that CPX-351 can contribute to long-term remission and improved overall survival in patients aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia. FUNDING: Jazz Pharmaceuticals.


Assuntos
Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Infusões Intravenosas , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária , Modelos de Riscos Proporcionais , Resultado do Tratamento
4.
Mol Cell ; 81(11): 2332-2348.e9, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33974912

RESUMO

Meningioma-1 (MN1) overexpression in AML is associated with poor prognosis, and forced expression of MN1 induces leukemia in mice. We sought to determine how MN1 causes AML. We found that overexpression of MN1 can be induced by translocations that result in hijacking of a downstream enhancer. Structure predictions revealed that the entire MN1 coding frame is disordered. We identified the myeloid progenitor-specific BAF complex as the key interaction partner of MN1. MN1 over-stabilizes BAF on enhancer chromatin, a function directly linked to the presence of a long polyQ-stretch within MN1. BAF over-stabilization at binding sites of transcription factors regulating a hematopoietic stem/progenitor program prevents the developmentally appropriate decommissioning of these enhancers and results in impaired myeloid differentiation and leukemia. Beyond AML, our data detail how the overexpression of a polyQ protein, in the absence of any coding sequence mutation, can be sufficient to cause malignant transformation.


Assuntos
Carcinogênese/genética , DNA Helicases/genética , Proteínas Intrinsicamente Desordenadas/genética , Leucemia Mieloide Aguda/genética , Proteínas Nucleares/genética , Transativadores/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Animais , Sequência de Bases , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Cromatina/patologia , DNA Helicases/metabolismo , Elementos Facilitadores Genéticos , Feminino , Regulação Leucêmica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Proteínas Intrinsicamente Desordenadas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Nucleares/metabolismo , Peptídeos/genética , Peptídeos/metabolismo , Mapeamento de Interação de Proteínas , Estabilidade Proteica , Transporte Proteico , Transdução de Sinais , Análise de Sobrevida , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo
5.
Cancer Invest ; 39(6-7): 550-558, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34027748

RESUMO

This study aimed to examine the prognostic significance of peripheral absolute monocyte count (AMC) in combination with absolute lymphocyte count (ALC) at the time of relapse in a cohort of 57 patients with early relapsed (first complete remission <12 months) acute myeloid leukemia (AML). Both univariate and multivariate Cox proportional hazard regression analyses revealed that normal AMC in combination with normal/high ALC (versus low/high AMC in combination with low ALC) was significantly associated with improved OS. We concluded that the combination of AMC and ALC could be used as a prognostic marker for survival outcomes in early relapsed AML.


Assuntos
Leucemia Mieloide Aguda/mortalidade , Leucócitos Mononucleares/metabolismo , Recidiva Local de Neoplasia/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mieloide Aguda/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Prognóstico , Análise de Regressão , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
6.
Leuk Res ; 106: 106584, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33933715

RESUMO

While dysregulation of MYC has been implicated in acute myeloid leukemia (AML), the impact of MYC protein expression in AML is less well understood. We investigated the correlation of MYC protein expression by immunohistochemistry (MYC-IHC) with MYC abnormalities and prognosis in adult de novo AML. MYC-IHC in bone marrow of patients with untreated AML (n = 58) was assessed and scored as MYClow (0-40 % of blasts) or MYChigh (> 40 % of blasts). This was correlated with MYC abnormalities by fluorescence in situ hybridization (FISH) and prognosis in the context of cytogenetic risk stratification. Residual myeloid disease at the end of induction was assessed by flow cytometry. MYClow and MYChigh were detected in 24 (41 %) and 34 cases (59 %), respectively. Extra copies of MYC were present in 12 % of cases and were not correlated with level of MYC-IHC. No cases had MYC translocation or amplification. Compared to MYClow patients, MYChigh patients had a shorter overall survival in all cytogenetic risk groups (68 vs. 21 months, p = 0.006) and in the intermediate risk group (61 vs. 21 months, p = 0.046). MYChigh patients had a tendency towards detected residual disease at the end of induction in all cytogenetic risk and intermediate risk groups. Regardless of the underlying mechanisms of MYC dysregulation, high level of MYC protein is expressed in the majority of AML and correlated to worse prognosis. Further studies on MYC dysregulation in leukemogenesis and therapy targeting MYC aberration are warranted.


Assuntos
Expressão Gênica , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Biomarcadores Tumorais , Análise Citogenética , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda/mortalidade , Prognóstico , Reprodutibilidade dos Testes
7.
Leuk Res ; 107: 106603, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33957373

RESUMO

Acute Myeloid Leukemia (AML) is a complex and highly aggressive disease. To characterize the prognostic factors of pediatric patients with AML relapse, a retrospective cohort study was performed to collect data from children and adolescents, at a hematological oncology reference center, over 11 years. We selected 51 cases of the disease, diagnosed and treated uniformly, divided into two groups: with complete remission (n = 33; 65 %) and with relapse (n = 18; 35 %). The groups were homogeneous concerning demographic characteristics and hematological parameters at diagnosis. AML M3 was the most common subtype (n = 19; 37 %) and was associated with a good prognosis. The highest rate of relapse was with AML M0 (n = 3 of 5 patients; 60 %). The most predominant gene mutation, FLT3-ITD, did not influence the prognosis in our study. The complete remission group presented a higher mean frequency of positive cells for the granulocytic marker CD13a at diagnosis. In cases with AML relapse, CD36, CD4, CD7, and CD22 were the most expressed markers. Increase incidence of recurrence was associated with CD7 (HR 1.035; p = 0.003), CD4 (HR 1.032, p = 0.001) and CD22 (HR 1.042; p = 0.049). Our results highlight the importance of analyzing immunophenotypic markers to help predict the outcome of AML in children and adolescents.


Assuntos
Biomarcadores Tumorais , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Linfócitos/metabolismo , Fatores Etários , Diagnóstico Diferencial , Gerenciamento Clínico , Granulócitos/metabolismo , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiologia , Linfócitos/imunologia , Mutação , Prognóstico , Resultado do Tratamento
8.
Hematology ; 26(1): 371-379, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33971800

RESUMO

OBJECTIVES: The outcome of elderly acute myeloid leukemia (AML) patients is poor, which was traditionally attributed to patient- and leukemia-related factors. However, studies about the genetic features of these elderly patients have not been integrated and the genetic mechanism of their poor outcome is less known. METHODS: Here, we used next generation sequencing (NGS) to identify the genetic features of elderly AML patients and confirmed the efficacy of chemotherapy based on molecular aberrations. Mutations in 111 genes relevant to hematological malignancy was analysed by virtue of NGS and the genetic differences were compared between elderly (n=52) and young (n=161) AML patients. Furthermore, the outcome of decitabine-based chemotherapy was identified in elderly patients. RESULTS: Frequencies of adverse genetic alterations, such as RUNX1 and secondary-type mutations (ASXL1, STAG2 and spliceosome), were much higher in elderly patients, while the frequency of WT1 mutations was much lower. Moreover, epigenetic mutations such as DNMT3A, TET2, ASXL1 and IDH2, were also more common in elderly patients. Furthermore, there were 39 elderly patients receiving the decitabine-based chemotherapy, and the results showed that the overall response rate (ORR) and complete remission rate (CR) were 76.9% and 71.8%, respectively. The median overall survival (OS) for those older patients was 12 months, and the 2-year OS probability was 20.5%. DISCUSSION: Our study provides deep understanding into the molecular mechanisms of the poor outcome of elderly AML patients. CONCLUSION: Epigenetic mutations play an important role, and decitabine-based regimen can be used as alternative first-line chemotherapy for elderly patients.


Assuntos
Decitabina/administração & dosagem , Leucemia Mieloide Aguda , Mutação , Proteínas de Neoplasias/genética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
9.
Nat Commun ; 12(1): 2482, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931647

RESUMO

While oncogenes promote tumorigenesis, they also induce deleterious cellular stresses, such as apoptosis, that cancer cells must combat by coopting adaptive responses. Whether tumor suppressor gene haploinsufficiency leads to such phenomena and their mechanistic basis is unclear. Here, we demonstrate that elevated levels of the anti-apoptotic factor, CASP8 and FADD-like apoptosis regulator (CFLAR), promotes apoptosis evasion in acute myeloid leukemia (AML) cells haploinsufficient for the cut-like homeobox 1 (CUX1) transcription factor, whose loss is associated with dismal clinical prognosis. Genome-wide CRISPR/Cas9 screening identifies CFLAR as a selective, acquired vulnerability in CUX1-deficient AML, which can be mimicked therapeutically using inhibitor of apoptosis (IAP) antagonists in murine and human AML cells. Mechanistically, CUX1 deficiency directly alleviates CUX1 repression of the CFLAR promoter to drive CFLAR expression and leukemia survival. These data establish how haploinsufficiency of a tumor suppressor is sufficient to induce advantageous anti-apoptosis cell survival pathways and concurrently nominate CFLAR as potential therapeutic target in these poor-prognosis leukemias.


Assuntos
Apoptose/genética , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Haploinsuficiência , Proteínas de Homeodomínio/metabolismo , Leucemia Mieloide Aguda/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/genética , Imunoprecipitação da Cromatina , Dipeptídeos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Genes Supressores de Tumor , Células-Tronco Hematopoéticas/metabolismo , Proteínas de Homeodomínio/genética , Humanos , Indóis/farmacologia , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Regiões Promotoras Genéticas , Análise Serial de Proteínas , Proteínas Repressoras/deficiência , Proteínas Repressoras/genética , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
10.
BMC Cancer ; 21(1): 475, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33926391

RESUMO

BACKGROUND: Acute myeloid leukemia (AML) remains one of the most common hematological malignancies, posing a serious challenge to human health. HSPA8 is a chaperone protein that facilitates proper protein folding. It contributes to various activities of cell function and also is associated with various types of cancers. To date, the role of HSPA8 in AML is still undetermined. METHODS: In this study, public datasets available from the TCGA (Cancer Genome Atlas) and GEO (Gene Expression Omnibus) were mined to discover the association between the expression of HSPA8 and clinical phenotypes of CN-AML. A series of bioinformatics analysis methods, including functional annotation and miRNA-mRNA regulation network analysis, were employed to investigate the role of HSPA8 in CN-AML. RESULTS: HSPA8 was highly expressed in the AML patients compared to the healthy controls. The high HSPA8 expression had lower overall survival (OS) rate than those with low HSPA8 expression. High expression of HSPA8 was also an independent prognostic factor for overall survival (OS) of CN-AML patients by multivariate analysis. The differential expressed genes (DEGs) associated with HSPA8 high expression were identified, and they were enriched PI3k-Akt signaling, cAMP signaling, calcium signaling pathway. HSPA8 high expression was also positively associated with micro-RNAs (hsa-mir-1269a, hsa-mir-508-3p, hsa-mir-203a), the micro-RNAs targeted genes (VSTM4, RHOB, HOBX7) and key known oncogenes (KLF5, RAN, and IDH1), and negatively associated with tumor suppressors (KLF12, PRKG1, TRPS1, NOTCH1, RORA). CONCLUSIONS: Our research revealed HSPA8 as a novel potential prognostic factor to predict the survival of CN-AML patients. Our data also revealed the possible carcinogenic mechanism and the complicated microRNA-mRNA network associated with the HSPA8 high expression in AML.


Assuntos
Proteínas de Choque Térmico HSC70/metabolismo , Leucemia Mieloide Aguda/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Biologia Computacional , AMP Cíclico/metabolismo , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Genes Supressores de Tumor , Estudo de Associação Genômica Ampla , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fenótipo , Fosfatidilinositol 3-Quinases/genética , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Análise de Sequência de RNA , Taxa de Sobrevida , Adulto Jovem
11.
Cancer Causes Control ; 32(7): 705-712, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33837498

RESUMO

PURPOSE: Racial disparities in acute myeloid leukemia (AML) have been reported but the relative contribution of disease versus patient-specific factors including comorbidities and access to care is unclear. METHODS: We conducted a retrospective analysis of patient characteristics, treatment patterns and outcomes in a racially diverse patient cohort controlling for cytogenetic risk group. Patients were classified into four groups: non-Hispanic White (NHW), non-Hispanic Black (NHB), Hispanic and Other. RESULTS: We evaluated 106 patients from 84 zipcodes incorporating demographics, clinicopathologic features, treatment patterns and outcomes. We identified significant differences in BMI and geographic poverty based on ethnoracial group, while prognostic mutations in NPM1 and FLT3 did not differ significantly. Utilization of intensive chemotherapy and transplant rate did not differ by ethnoracial group. However, there was a significantly higher use of alternate donor transplants in minority populations. There was a notably increased rate of clinical trial enrollment in NHW patients compared to other groups. In log-rank analysis, NHW patients had increased overall survival (OS) compared to NHB, Hispanic and Other patients (31.6 months vs. 16.7 months vs. 14.3 months, vs 18.1 months, p = 0.021). In bivariate analysis, overall survival was negatively influenced by advanced age and race. Obesity and zip code poverty levels approached statistical significance in predicting OS. In multivariate analysis, the only factors independently influencing OS were race and allogeneic stem cell transplant. CONCLUSION: These results suggest that race impacts survival in intermediate-risk AML, highlighting the need to dissect biologic and nonbiologic factors that contribute to this disparity.


Assuntos
Afro-Americanos/estatística & dados numéricos , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Hispano-Americanos/estatística & dados numéricos , Leucemia Mieloide Aguda/mortalidade , Avaliação de Resultados da Assistência ao Paciente , Adulto , Idoso , Aloenxertos , Biomarcadores Tumorais/genética , Estudos de Coortes , Humanos , Leucemia Mieloide Aguda/etnologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Grupos Minoritários/estatística & dados numéricos , Mutação , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Resultado do Tratamento
13.
Aging (Albany NY) ; 13(8): 11988-12006, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33891561

RESUMO

Acute myeloid leukemia (AML) is a frequent malignancy in adults worldwide; identifying preferable biomarkers has become one of the current challenges. Given that COMMD7 has been reported associated with tumor progression in various human solid cancers but rarely reported in AML, herein, RNA sequencing data from TCGA and GTEx were obtained for analysis of COMMD7 expression and differentially expressed gene (DEG). Furthermore, functional enrichment analysis of COMMD7-related DEGs was performed by GO/KEGG, GSEA, immune cell infiltration analysis, and protein-protein interaction (PPI) network. In addition, the clinical significance of COMMD7 in AML was figured out by Kaplan-Meier Cox regression and prognostic nomogram model. R package was used to analyze incorporated studies. As a result, COMMD7 was highly expressed in various malignancies, including AML, compared with normal samples. Moreover, high expression of COMMD7 was associated with poor prognosis in 151 AML samples, as well as subgroups with age >60, NPM1 mutation-positive, FLT3 mutation-negative, and DNMT3A mutation-negative, et al. (P < 0.05). High COMMD7 was an independent prognostic factor in Cox regression analysis; Age and cytogenetics risk were included in the nomogram prognostic model. Furthermore, a total of 529 DEGs were identified between the high- and the low- expression group, of which 92 genes were up-regulated and 437 genes were down-regulated. Collectively, high expression of COMMD7 is a potential biomarker for adverse outcomes in AML. The DEGs and pathways recognized in the study provide a preliminary grasp of the underlying molecular mechanisms of AML carcinogenesis and progression.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Biomarcadores Tumorais/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/mortalidade , Biologia Computacional , Conjuntos de Dados como Assunto , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Mapas de Interação de Proteínas/genética , RNA-Seq , Regulação para Cima
14.
Cancer Med ; 10(9): 2946-2955, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33787078

RESUMO

Most acute myeloid leukemia (AML) cells are argininosuccinate synthetase-deficient. Pegylated arginine deiminase (ADI-PEG20) monotherapy depletes circulating arginine, thereby selectively inducing tumor cell death. ADI-PEG20 was shown to induce complete responses in ~10% of relapsed/refractory or poor-risk AML patients. We conducted a phase I, dose-escalation study combining ADI-PEG20 and low-dose cytarabine (LDC) in AML patients. Patients received 20 mg LDC subcutaneously twice daily for 10 days every 28 days and ADI-PEG20 at 18 or 36 mg/m2 (dose levels 1 and 2) intramuscularly weekly. An expansion cohort for the maximal tolerated dose of ADI-PEG20 was planned to further estimate the toxicity and preliminary response of this regimen. The primary endpoints were safety and tolerability. The secondary endpoints were time on treatment, overall survival (OS), overall response rate (ORR), and biomarkers (pharmacodynamics and immunogenicity detection). Twenty-three patients were included in the study, and seventeen patients were in the expansion cohort (dose level 2). No patients developed dose-limiting toxicities. The most common grade III/IV toxicities were thrombocytopenia (61%), anemia (52%), and neutropenia (30%). One had an allergic reaction to ADI-PEG20. The ORR in 18 evaluable patients was 44.4%, with a median OS of 8.0 (4.5-not reached) months. In seven treatment-naïve patients, the ORR was 71.4% and the complete remission rate was 57.1%. The ADI-PEG20 and LDC combination was well-tolerated and resulted in an encouraging ORR. Further combination studies are warranted. (This trial was registered in ClinicalTrials.gov as a Ph1 Study of ADI-PEG20 Plus Low-Dose Cytarabine in Older Patients With AML, NCT02875093).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/efeitos adversos , Hidrolases/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Polietilenoglicóis/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Arginina/efeitos dos fármacos , Arginina/metabolismo , Argininossuccinato Sintase/deficiência , Citarabina/administração & dosagem , Citarabina/farmacocinética , Esquema de Medicação , Feminino , Humanos , Hidrolases/administração & dosagem , Hidrolases/farmacocinética , Injeções Intramusculares , Injeções Subcutâneas , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , Trombocitopenia/induzido quimicamente , Resultado do Tratamento
15.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669431

RESUMO

Several immune checkpoint molecules and immune targets in leukemic cells have been investigated. Recent studies have suggested the potential clinical benefits of immuno-oncology (IO) therapy against acute myeloid leukemia (AML), especially targeting CD33, CD123, and CLL-1, as well as immune checkpoint inhibitors (e.g., anti-PD (programmed cell death)-1 and anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) antibodies) with or without conventional chemotherapy. Early-phase clinical trials of chimeric antigen receptor (CAR)-T or natural killer (NK) cells for relapsed/refractory AML showed complete remission (CR) or marked reduction of marrow blasts in a few enrolled patients. Bi-/tri-specific antibodies (e.g., bispecific T-cell engager (BiTE) and dual-affinity retargeting (DART)) exhibited 11-67% CR rates with 13-78% risk of cytokine-releasing syndrome (CRS). Conventional chemotherapy in combination with anti-PD-1/anti-CTLA4 antibody for relapsed/refractory AML showed 10-36% CR rates with 7-24 month-long median survival. The current advantages of IO therapy in the field of AML are summarized herein. However, although cancer vaccination should be included in the concept of IO therapy, it is not mentioned in this review because of the paucity of relevant evidence.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoconjugados/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunoterapia Adotiva/métodos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Humanos , Proteínas de Checkpoint Imunológico/metabolismo , Leucemia Mieloide Aguda/metabolismo , Taxa de Sobrevida
17.
Leuk Res ; 103: 106539, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33647818

RESUMO

BACKGROUND: Acute leukemia with mixed-phenotype blasts is associated with poor outcomes. There are no standard treatment regimens. Due to disease heterogeneity, controversy exists over whether an AML-based, ALL-based, or a combined (hybrid) AML/ALL-based regimen is most appropriate. MATERIALS AND METHODS: We conducted a single-center, retrospective case series review of patients with acute leukemia with mixed phenotype blasts as described by the European Group for Immunological Characterization of Leukemia (EGIL) or the 2008 WHO classification. Patients were treated from November 2014 and December 2019 with the combination chemotherapy regimen FLAG-idarubicin-vincristine-prednisone with or without rituximab. Outcomes included induction response, time to transplant, time to relapse, overall survival, time to neutrophil or platelet recovery, infection, and duration of hospitalization. RESULTS: The median age was 68 years (range 21-77). Six patients (87.5 %) had unfavorable/complex cytogenetics. All patients achieved a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi). Estimated 1-year overall survival was 85.7 %. There were no deaths during induction, with a 22 day median duration of hospitalization for induction. CONCLUSION: The combination of FLAG, idarubicin, vincristine, and prednisone (FLAG-VIPR) demonstrated favorable induction responses in a disease state with historically poor outcomes and should be studied in a prospective clinical trial.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Mieloide Aguda , Prednisona/administração & dosagem , Vidarabina/análogos & derivados , Vincristina/administração & dosagem , Adulto , Idoso , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Vidarabina/administração & dosagem
18.
Leuk Res ; 103: 106540, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33667811

RESUMO

Recent advancements in next-generation sequencing (NGS) technologies allow the simultaneous identification of targeted copy number alterations (CNAs) as well as somatic mutations using the same panel-based NGS data. We investigated whether CNAs detected by the targeted NGS data provided additional clinical implications, over somatic mutations, in myelodysplastic syndrome (MDS). Targeted deep sequencing of 28 well-known MDS-related genes was performed for 266 patients with MDS. Overall, 215 (80.8 %) patients were found to have at least one somatic mutation; 67 (25.2 %) had at least one CNA; 227 (85.3 %) had either a somatic mutation or CNA; and 12 had CNA without somatic mutations. Considering the clinical variables and somatic mutations alone, multivariate analysis demonstrated that sex, revised International Prognostic Scoring System (IPSS-R), and NRAS and TP53 mutations were independent prognostic factors for overall survival. For AML-free survival, these factors were sex, IPSS-R, and mutations in NRAS, DNMT3A, and complex karyotype/TP53 mutations. When we consider clinical variables along with somatic mutations and CNAs, genetic alterations in TET2, LAMB4, U2AF1, and CBL showed additional significant impact on the survivals. In conclusion, our study suggests that the concurrent detection of somatic mutations and targeted CNAs may provide clinically useful information for the prognosis of MDS patients.


Assuntos
Variações do Número de Cópias de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Síndromes Mielodisplásicas , Proteínas de Neoplasias/genética , Adolescente , Adulto , Idoso , Criança , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Taxa de Sobrevida
19.
Medicine (Baltimore) ; 100(8): e24614, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33663070

RESUMO

ABSTRACT: To investigate the prognostic value of the circulating peripheral blood cell counts changes in acute myeloid leukemia (AML) at different time points during induction chemotherapy.We retrospectively analyzed the clinical and laboratory data of 237 newly diagnosed AML patients admitted to Fujian Medical University Union Hospital from January 2011 to December 2014.1. When primitive cells were first removed from the circulating peripheral blood, it was called peripheral blood blast clearance (PBBC). These patients were divided into two groups, according to PBBC. Statistical analysis showed that the day 5 of induction chemotherapy was a better cut-off for PBBC. PBBC≤5 days is defined as early-blast-clearance, while PBBC >6 days is delayed-blast-clearance. There was significant difference between the two groups on complete remission (CR) rate (P = .002), recurrence-free survival (RFS) (P = .026) and overall survival (OS) (P = .001). 2. Multivariate analysis suggested PBBC is an independent prognostic factor for CR, RFS, and OS in AML. Receiver operating characteristic(ROC) curve analysis showed the CR rate of patients with white blood cell count less than 1.25 × 109/L was significantly higher than that of patients with white blood cell count more than 1.25 × 10 9/L (P < .001) at day 5 of induction chemotherapy, but the RFS and OS was no significantly different (P > .05).The dynamics of peripheral blood blast in AML after initiation of induction chemotherapy, especially the time length to achieve PBBC, has important prognostic value for CR rate, RFS, and OS in AML patients. It is a simple and feasible method to evaluate the efficacy of AML.


Assuntos
Crise Blástica/patologia , Quimioterapia de Indução/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Contagem de Leucócitos/métodos , Adolescente , Adulto , Idoso , China , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Curva ROC , Recidiva , Estudos Retrospectivos , Análise de Sobrevida , Fatores de Tempo , Adulto Jovem
20.
BMC Cancer ; 21(1): 277, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33722210

RESUMO

BACKGROUND: As one of the novel molecules, circRNA has been identified closely involved in the pathogenesis of many diseases. However, the function of circRNA in acute myeloid leukemia (AML) still remains unknown. METHODS: In the current study, the RNA expression profiles were obtained from Gene Expression Omnibus (GEO) datasets. The differentially expressed RNAs were identified using R software and the competing endogenous RNA (ceRNA) network was constructed using Cytoscape. Functional and pathway enrichment analyses were performed to identify the candidate circRNA-mediated aberrant signaling pathways. The hub genes were identified by MCODE and CytoHubba plugins of Cytoscape, and then a subnetwork regulatory module was established. RESULTS: A total of 27 circRNA-miRNA pairs and 208 miRNA-mRNA pairs, including 12 circRNAs, 24 miRNAs and 112 mRNAs were included in the ceRNA network. Subsequently, a subnetwork, including 4 circRNAs, 5 miRNAs and 6 mRNAs, was established based on related circRNA-miRNA-mRNA regulatory modules. CONCLUSIONS: In summary, this work analyzes the characteristics of circRNA as competing endogenous RNA in AML pathogenesis, which would provide hints for developing novel prognostic, diagnostic and therapeutic strategy for AML.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Leucemia Mieloide Aguda/genética , RNA Circular/metabolismo , Biomarcadores Tumorais/análise , Biologia Computacional , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , MicroRNAs/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/genética , RNA Circular/análise , RNA Mensageiro/metabolismo , Transdução de Sinais/genética , Análise de Sobrevida
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