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1.
Rinsho Ketsueki ; 62(8): 1308-1318, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497221

RESUMO

Leukemias diagnosed in <1-year-old infants generally have an aggressive clinical nature and unique biological characteristics. Acute lymphoblastic leukemia (ALL) in infants is still intractable and difficult to treat as compared with other pediatric ALLs, for which considerable progress in treatment outcomes has been recently achieved. Infant leukemia cells frequently carry chromosome translocations involving the 11q23 locus, resulting in the rearrangement and fusion of the KMT2A (MLL) gene. Among several KMT2A fusion genes, KMT2A-AFF1 (MLL-AF4) fusion is characteristically observed in neonatal and infant ALL, representing a hallmark of poor prognosis. The cytogenetic/molecular abnormalities t (1;22)(p13.3;q13.1)/RBM15-MKL1 and t (8;16)(p11.2;p13.3)/KAT6A-CREBBP (MOZ-CBP) are also well-known in acute myeloblastic leukemia in this population. Although many neonatal leukemias occurring within the first 28 days of birth are refractory, spontaneous remissions are occasionally observed, especially in the case of t (8;16). Therefore, international collaborative studies are necessary to improve understanding and facilitate the development of better treatment for this rare disease. Thus, this study summarizes the recently reported clinical, cytogenetic, and molecular biology aspects of neonatal and infant leukemias.


Assuntos
Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Aberrações Cromossômicas , Humanos , Lactente , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Translocação Genética
2.
Rinsho Ketsueki ; 62(8): 883-891, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497227

RESUMO

Almost all genetic abnormalities involved in the occurrence and progression of myelodysplastic syndromes (MDS) and acute myeloid leukemia have been reported within the last decade. The molecular mechanisms of these genetic changes involved in causing dysfunctions in hematopoietic cells have also been clarified in recent years. For MDS, gene mutations of RNA splicing factors and cohesin complex have been shown to trigger not only aberrant RNA splicing or decreased chromatin insulation but also DNA damage response and transcriptional dysregulation through inefficient interaction between promoters and enhancers. Consequently, these newly identified disease-causing mechanisms may be considered potential therapeutic targets.


Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Síndromes Mielodisplásicas/genética , Splicing de RNA , Fatores de Processamento de RNA/genética
3.
Rinsho Ketsueki ; 62(8): 954-966, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497236

RESUMO

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene represent the most common genetic alteration in acute myeloid leukemia (AML), identified in approximately one third of patients newly diagnosed with AML. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple inhibitors of FLT3 signaling have been developed in the last few years with variable kinase-inhibitory properties, pharmacokinetics, and toxicity profiles. At present, two FLT3 inhibitors (gilteritinib and quizartinib) have been approved as monotherapies for relapsed/refractory FLT3-mutated AML in Japan, and many more drugs are currently being researched in clinical trials as monotherapies or in combination with conventional chemotherapy or hypomethylating agents and in various settings, including front line, relapsed/refractory disease, and maintenance therapy after consolidation chemotherapy or allogeneic stem cell transplantation. Despite significant advances, some issues need to be overcome, including the resistance to FLT3 inhibitors and controversies regarding the role of FLT3 inhibitors in maintenance therapies and the role of allogeneic stem cell transplantation in FLT3-mutated AML.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva , Tirosina Quinase 3 Semelhante a fms/genética
4.
Rinsho Ketsueki ; 62(8): 967-977, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497237

RESUMO

The etiology and pathogenesis of acute myeloid leukemia (AML) have been elucidated at chromosomal and genetic levels. The classification and prognosis for its treatment has clearly involved specific chromosomal aberrations and genetic mutations. The recent comprehensive genomic analysis represented by next-generation sequencers has led to discovering new genetic mutations in AML. These findings have not only been applied clinically as prognostic factors and MRD markers but also contributed to the development of new molecular-targeting drugs. Many new drugs have already been approved in the USA and Europe, and new stratified treatments have tried to incorporate them. With the advent of venetoclax, treatment strategies, especially for patients with poor prognosis and who are unfit, have been substantially revised, and the maintenance therapy for AML is also being reevaluated in accordance to the National Comprehensive Cancer Network guidelines. This article will review the current status of AML treatment in Japan and according to Western guidelines.


Assuntos
Leucemia Mieloide Aguda , Aberrações Cromossômicas , Genômica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico
5.
Hematology ; 26(1): 565-576, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34384344

RESUMO

Objectives: Multipotent mesenchymal stromal cells (MSC) play a pivotal role in the bone marrow (BM) niche. Stanniocalcin 1 (STC1) secreted by MSC has been demonstrated to promote the survival of neoplastic cells and was suggested a marker for minimal residual disease of acute myeloid leukemia (AML). Therefore, we evaluated the expression of STC1 in MSC from AML patients (MSCAML) compared to MSC from healthy donors (MSCHD).Methods: Liquid culture assays of MSCAML and MSCHD were performed to compare expansion capacity. Gene expression profiles of MSCAML vs. MSCHD were established. Secretion of STC1 was tested by ELISA in MSCAML vs. MSCHD and expression of STC1 in AML- vs. HD-BM by immunohistochemistry. In addition, co-cultures of AML cells on MSC were initiated and ultrastructural intercellular communication patterns were investigated. Finally, the effect of blocking STC1 on AML cells was evaluated.Results: MSCAML showed significant decreased expansion capacity compared to MSCHD. Gene analysis revealed marked overexpression of STC1 in MSCAML. ELISA and immunohistochemical findings confirmed this observation. Electron microscopy analysis showed reciprocal stimulation between AML cells and MSC. Blockade of STC1 did not significantly affect AML cell proliferation and apoptosis.Discussion: Characteristics of MSC differ depending on whether they originate from AML patients or from HD. STC1 was mostly overexpressed in MSCAML compared to MSCHD. In vitro blockade of STC1, however, was not associated with AML cell proliferation and apoptosis.Conclusion: Differences in expression levels of glycoproteins from MSCAML compared to MSCHD not necessarily assume that these molecules are niche-relevant in leukemic disease.


Assuntos
Glicoproteínas/genética , Leucemia Mieloide Aguda/genética , Células-Tronco Mesenquimais/patologia , Regulação para Cima , Adulto , Idoso , Células Cultivadas , Feminino , Glicoproteínas/análise , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Células Tumorais Cultivadas
6.
Zhonghua Yu Fang Yi Xue Za Zhi ; 55(8): 983-989, 2021 Aug 06.
Artigo em Chinês | MEDLINE | ID: mdl-34445837

RESUMO

Objective: To figure out the association between the expression of m6A RNA methylation regulators and the prognosis of children AML, and provide genetic markers for monitoring the progression and recurrence of AML. Methods: Twenty two m6A RNA methylation regulators were firstly analyzed using the data from Therapeutically Applicable Research To Generate Effective Treatments(TARGET) database and The Genotype-Tissue Expression(GTEx) database, Wilcoxon rank test was performed to analyze the differentially expression of m6A RNA methylation regulators between the AML and normal tissue, 296 AML children were divided into training cohort and validation cohort by simple random sampling method, Lasso regression was used to screen out the risk factors and the multivariate Cox regression was applied for establishing prognosis predicting model in training cohort. Kaplan-Meier survival curve, time-dependent ROC curve and multivariate Cox regression were used to estimate the efficiency of risk score calculated by predictive model in validation cohort. Results: Twenty one m6A genes were up regulated in AML compared to Normal patients. Five m6A RNA methylation regulators(ZC3H13, YTHDC2, HNRNPA2B1, METTL3, METTL5) were included in final predicting model. Risk score could independently predict the survival of AML patients in training cohort(HR:2.72, 95%CI: 1.54-4.81, P=0.000 6) and validation cohort(HR:2.01, 95%CI:1.14-3.50, P=0.016). Low-risk patients had better prognoses than high-risk patients both in training cohort(P=0.001 9) and validation cohort(P=0.023). Conclusion: This prognosis predicting model constructed by m6A RNA methylation regulators could independently predict the survival prognosis in AML children, and should be helpful for clinical therapy.


Assuntos
Leucemia Mieloide Aguda , Criança , Estudos de Coortes , Humanos , Leucemia Mieloide Aguda/genética , Metilação , RNA , RNA Helicases
7.
Medicine (Baltimore) ; 100(32): e26740, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397877

RESUMO

BACKGROUND: Acute leukemia (AL) is a kind of malignant tumor of hematopoietic system. A number of studies have suggested that Single Nucleotide Polymorphisms are significantly associated with risk of AL. Present study performs meta-analysis to evaluate the association between CYP2B6 c.516G>T variant and AL risk. METHODS: Databases including PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI), and Wanfang were searched for literatures to September 30, 2019, both in English and Chinese. Relative risk and its 95% confidence intervals were used to assess the associations. Statistical analyses of this meta-analysis were conducted by using STATA 13.0. software. RESULTS: A total of 7 studies, including 1038 cases and 1648 controls, were analyzed. Our results indicated that CYP2B6 c.516G>T variant was significantly related to an increased the risk of AL under dominant model, recessive model, homozygote model, and allelic model. In addition, subgroup analyses were also performed by disease classification, country, and study design. No significant associations were obtained between CYP2B6 c.516G>T variant and the risk of AL under the recessive model in the design of hospital-based (relative risk = 0.98; 95% confidence interval: 0.95-1.01; P  = 0.118). CONCLUSION: Our meta-analysis indicated that the CYP2B6 variant is significantly associated with AL risk, in which CYP2B6 c.516G>T is related to an increased risk of AL.


Assuntos
Citocromo P-450 CYP2B6/genética , DNA de Neoplasias/genética , Predisposição Genética para Doença , Leucemia Mieloide Aguda/genética , Polimorfismo de Nucleotídeo Único , Alelos , Citocromo P-450 CYP2B6/metabolismo , Humanos , Leucemia Mieloide Aguda/metabolismo
8.
Zhonghua Xue Ye Xue Za Zhi ; 42(6): 480-486, 2021 Jun 14.
Artigo em Chinês | MEDLINE | ID: mdl-34384154

RESUMO

Objective: To analyze the genetic landscape of multiple fusion genes in patients with de novo acute myeloid leukemia (AML) and investigate the characteristics of immunophenotypes and mutations. Methods: The results of multiple fusion genes from 4192 patients with de novo AML were retrospectively analyzed from 2016 to 2020. In addition, the immunophenotypical data and the mutational results from high-through put method were statistically investigated and correlated as well. Results: ①Among the 52 targets, 29 different types of fusion genes were detected in 1948 patients (46.47%) with AML, which demonstrated an "exponential distribution" . ② As the age increased, the number of patients with fusion gene increased first and then decreased gradually. The total incidence rate of fusion genes and MLL rearrangment in children were significantly higher than those in adults (69.18% vs 44.76%, 15.35% vs 8.36%) . ③The mutations involving FLT3 and RAS signaling pathway contributed most in patients with MLL rearrangment. ④No specific immunophenotypic characteristics were found in AML patients with MLL or NUP98 rearrangements. Conclusion: Nearly half of AML patients were accompanied by specific fusion gene expression, the proportions of different fusion genes in pediatric and adults patients were different by multiple PCR. The gene mutations and immunophenotype of these AML patients have certain rules.


Assuntos
Leucemia Mieloide Aguda , Adulto , Criança , Expressão Gênica , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda/genética , Mutação , Proteína de Leucina Linfoide-Mieloide/genética , Estudos Retrospectivos
9.
Blood Adv ; 5(17): 3254-3265, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34448812

RESUMO

Splicing factor (SF) mutations are important contributors to the pathogenesis of hematological malignancies; however, their relevance in risk classification of acute myeloid leukemia (AML) warrants further investigation. To gain more insight into the characteristics of patients with AML carrying SF mutations, we studied their association with clinical features, cytogenetic and molecular abnormalities, and clinical outcome in a large cohort of 1447 patients with AML and high-risk myelodysplastic syndrome. SF mutations were identified in 22% of patients and were associated with multiple unfavorable clinical features, such as older age, antecedent myeloid disorders, and adverse risk factors (mutations in RUNX1 and ASXL1). Furthermore, they had significantly shorter event-free and overall survival. Notably, in European LeukemiaNet (ELN) 2017 favorable- and intermediate-risk groups, SF3B1 mutations were indicative of relatively poor prognosis. In addition, patients carrying concomitant SF mutations and RUNX1 mutations had a particularly adverse prognosis. In patients without any of the 4 most common SF mutations, RUNX1 mutations were associated with relatively good outcome, which was comparable to that of intermediate-risk patients. In this study, we propose that SF mutations be considered for incorporation into prognostic classification systems. First, SF3B1 mutations could be considered an intermediate prognostic factor when co-occurring with favorable risk features and as an adverse prognostic factor for patients currently categorized as having intermediate risk, according to the ELN 2017 classification. Second, the prognostic value of the current adverse factor RUNX1 mutations seems to be limited to its co-occurrence with SF mutations.


Assuntos
Leucemia Mieloide Aguda , Idoso , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico , Fatores de Processamento de RNA/genética , Fatores de Risco
10.
Blood Adv ; 5(17): 3279-3289, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34459887

RESUMO

The tyrosine-protein phosphatase nonreceptor type 11 (PTPN11) is an important regulator of RAS signaling and frequently affected by mutations in patients with acute myeloid leukemia (AML). Despite the relevance for leukemogenesis and as a potential therapeutic target, the prognostic role is controversial. To investigate the prognostic impact of PTPN11 mutations, we analyzed 1529 adult AML patients using next-generation sequencing. PTPN11 mutations were detected in 106 of 1529 (6.93%) patients (median VAF: 24%) in dominant (36%) and subclonal (64%) configuration. Patients with PTPN11 mutations were associated with concomitant mutations in NPM1 (63%), DNMT3A (37%), and NRAS (21%) and had a higher rate of European LeukemiaNet (ELN) favorable cytogenetics (57.8% vs 39.1%; P < .001) and higher white blood cell counts (P = .007) compared with PTPN11 wild-type patients. In a multivariable analysis, PTPN11 mutations were independently associated with poor overall survival (hazard ratio [HR]: 1.75; P < .001), relapse-free survival (HR: 1.52; P = .013), and a lower rate of complete remission (odds ratio: 0.46; P = .008). Importantly, the deleterious effect of PTPN11 mutations was confined predominantly to the ELN favorable-risk group and patients with subclonal PTPN11 mutations (HR: 2.28; P < .001) but not found with dominant PTPN11 mutations (HR: 1.07; P = .775), presumably because of significant differences within the rate and spectrum of associated comutations. In conclusion, our data suggest an overall poor prognostic impact of PTPN11 mutations in AML, which is significantly modified by the underlying cytogenetics and the clonal context in which they occur.


Assuntos
Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutação , Fosfoproteínas Fosfatases , Prognóstico , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Indução de Remissão
12.
Rinsho Ketsueki ; 62(7): 721-726, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34349054

RESUMO

A 38-year-old woman was referred to our hospital because of fever, general malaise, and abnormal blood count. The white blood cell count was 19,500/µl, with 72% lymphoblast. Bone marrow examination showed increased cellularity with 94% lymphoblast. Flow cytometry revealed the following T-cell lineages: cyCD3 (+), CD5 (+), CD7 (+), and CD34 (+). Chromosome analysis revealed hypodiploidy. The patient was diagnosed with early T-cell precursor lymphoblastic leukemia (ETP-ALL). After two cycles of induction chemotherapy, she achieved complete remission, but the disease relapsed after one cycle of consolidation therapy. At the time of relapse, leukemic cells were myeloperoxidase positive and showed a loss of T-cell surface antigen, suggesting that a lineage switch occurred. The patient did not respond to the second induction therapy. She subsequently received 3+7 (idarubicin+cytarabine) for acute myeloid leukemia (AML), but she deceased due to refractory leukemia. At the time of relapse, genome sequencing was performed and mutations of NRAS, TP53, and MLLT-PICALM fusion genes were revealed. Here, we report a case of ETP-ALL who relapsed with a lineage switch to AML in concordance with refractory disease.


Assuntos
Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Feminino , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Recidiva
13.
Rinsho Ketsueki ; 62(7): 774-780, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34349062

RESUMO

Genetic complexity and heterogeneity have made drug discovery difficult in human malignancies. In the past few years, we aimed to find vulnerabilities in therapy-resistant and refractory acute myeloid leukemia (AML) through integrative analyses of genomic data, clinical information, and results from in vivo/in vitro cell biological assays. Through analyses, we found that the cells of patients with AML show distinct sensitivity/resistance to small inhibiting molecules for anti-apoptosis and cell cycle/division. In particular, AML cells harboring the IDH1/2 mutations were highly sensitive to BCL-2 inhibition, while inhibition of IAP proteins resulted in efficient elimination of AML cells with varied FLT3, NRAS, and CBL mutations. Linking AML-initiating events with appropriate therapeutic strategies through cellular and genomic analyses might be further translated into nonmyeloid malignancies and solid tumors in the future.


Assuntos
Leucemia Mieloide Aguda , Transcriptoma , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico , Tirosina Quinase 3 Semelhante a fms/genética
14.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(4): 1011-1018, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34362476

RESUMO

OBJECTIVE: To the clinical characteristics and prognostic value of the patients with complete deletion of TET_JBP domain (ΔJBP) in TET2 acute myeloid leukemia (AML). METHODS: Next Generation Sequencing technology was used to determine the mutations of 34 AML-related genes (including TET2 gene). The I-TASSER tool was used to predict the tertiary structure of the full-length TET2 protein and TET_JBP structure deletion. RESULTS: Among 38 AML patients with TET2 mutations, 22(57.9%) showed truncation mutations, of which 16 (72.7%) produced TET2ΔJBP truncation mutants. Protein structure prediction showed that the deletion of TET_JBP domain lead to the significant changes of tertiary structure in TET2 protein. Compared with the patients in non-ΔJBP group, the age of patients in ΔJBP group were older (63 vs 54 years old, P=0.047), and the occurrence rate of CEBPA double mutation (CEBPAdm) were more frequency (31.3% vs 0, P=0.009), the complete remission (CR) rate after induction chemotherapy(37.5% vs 81.8%, P=0.008) were lower, the median EFS (5 vs 19 months, P=0.000) and median OS (16 vs 22 months, P=0.041) were shorter. Univariate analysis showed that platelets <50×109/L (P=0.004) and CEBPAdm (P=0.001) were related to the shorter OS of the patients. Further COX multivariate analysis showed that CEBPAdm is an independent prognostic factors of OS in TET2ΔJBP patients (P=0.010). In addition, ΔJBP patients with CEBPAdm showed lower hemoglobin levels (62 vs 75g/L, P=0.030) and lower median OS (9 months vs 18 months, P=0.000) than the patients without CEBPAdm. CONCLUSION: AML patients with TET2ΔJBP truncation mutant shows lower CR rate, shorter EFS and OS after induction chemotherapy, which may be related to the poor prognosis, and co-mutation with CEBPAdm, which is the independent prognostic factors of OS in AML patients with TET2ΔJBP.


Assuntos
Leucemia Mieloide Aguda , Proteínas de Ligação a DNA/genética , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Pessoa de Meia-Idade , Mutação , Prognóstico , Proteínas Proto-Oncogênicas/genética , Indução de Remissão
15.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(4): 1034-1038, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34362479

RESUMO

OBJECTIVE: To study the effects of FLT3-ITD length on 32D cell proliferation, apoptosis and sensitivity to FLT3 inhibitor, so as to provide references for stepwise therapy of FLT3-ITD mutated acute myeloid leukemia patients. METHODS: Three different FLT3-ITD mutants with same or adjacent insert sites were selected and constructed in an eukaryotic expression vector. FLT3-ITD mutants stably expressed 32D cell strains were selected with the help of lentivirus system and IL3 free cell culture medium. The proliferation and apoptosis of 32D cell strains after AC220 treatment were detected. RESULTS: FLT3-ITD mutants (ITD1, ITD2 and ITD3) stably expressed 32D cell strains were constructed successfully. In the absence of IL3 factor, the proliferation number of ITD1, ITD2 and ITD3 cell strains were mounted up to 2.3 folds, 3.7 folds, and 4.3 folds after 48 hours, respectively. Under the exposure of FLT3 inhibitor AC220, the IC50 values was 0.183, 0.446 and 0.836 nmol/L, and apoptosis rates was 88.6%, 34.2% and 16.1%, respectively. CONCLUSION: FLT3-ITD mutant expressed cell strains with longer ITD show higher capacity of proliferation and higher tolerance to AC220 treatment.


Assuntos
Leucemia Mieloide Aguda , Sequências de Repetição em Tandem , Apoptose , Proliferação de Células , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Inibidores de Proteínas Quinases , Tirosina Quinase 3 Semelhante a fms/genética
17.
J Coll Physicians Surg Pak ; 31(8): 941-946, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34320712

RESUMO

OBJECTIVE: To determine the expression levels of GPX1, SOCS5 and IL7 and their clinical significance in patients with acute myeloid leukaemia (AML). STUDY DESIGN: A case-control study. PLACE AND DURATION OF STUDY: Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China, from January 2013 to November 2020. METHODOLOGY: Based on the bioinformatics analysis, the expression levels of GPX1, SOCS5 and IL7 in the bone marrow of 64 AML patients (non-M3) and 32 healthy individuals were evaluated by real-time PCR. Correlation between GPX1 expression and the clinical characteristics, response to induced chemotherapy, and survival time of AML patients were analysed as the outcome measure. RESULTS: GPX1 was significantly downregulated in AML patients, which helped in distinguishing AML patients from normal controls. The area under the curve (AUC) of the receiver operator characteristic (ROC) was 0.741 (p <0.001). Additionally, GPX1 expression was correlated with gender (r = -0.250, p = 0.045), FAB classification (r = -0.332,  p = 0.004), and chemotherapy response (r = 0.366, p = 0.003). AML patients with high GPX1 expression levels had a lower rate of remission (p = 0.021) and poor long-term survival (p = 0.036) than those with low GPX1 expression levels. CONCLUSION: Low GPX1 expression in AML patients may be closely associated with the pathogenesis and chemoresistance of AML. Key Words: Acute myeloid leukaemia, Clinical outcome, Gene expression, GPX1.


Assuntos
Leucemia Mieloide Aguda , Medula Óssea , Estudos de Casos e Controles , China/epidemiologia , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real
18.
Rinsho Ketsueki ; 62(5): 486-495, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34248126

RESUMO

Relapse is an issue of concern for patients with acute myeloid leukemia and myelodysplastic syndromes (AML/MDS) who underwent allogeneic hematopoietic stem cell transplantation (allo HSCT). The conventional minimal residual disease (MRD) test of the bone marrow has serious limitations regarding invasiveness and applicability. To address this problem, we investigated the utility of a novel MRD test using tumor-derived fragmentary DNA, or circulating tumor DNA (ctDNA) for the identification of patients with high risk of AML/MDS relapse after undergoing myeloablative allo HSCT. We retrospectively collected tumor specimens and available matched serum samples at diagnosis and at 1 and 3 months post-allo HSCT from 53 patients with AML/MDS. After identifying driver mutations in 51 patients using next-generation sequencing, we designed at least one personalized digital polymerase chain reaction assay per case. Diagnostic ctDNA and matched tumor DNA exhibited excellent correlations with variant allele frequencies. Sixteen patients relapsed after a median of 7 months post allo HSCT. Both the mutation persistence in the bone marrow at 1 and 3 months post allo HSCT and the corresponding ctDNA persistence in the matched serum were comparably associated with higher 3-year cumulative incidence of relapse rates. These results demonstrate, for the first time, the utility of ctDNA as a noninvasive prognostic biomarker in patients with AML/MDS who underwent allo HSCT.


Assuntos
DNA Tumoral Circulante , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Prognóstico , Estudos Retrospectivos , Transplante Homólogo
19.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299222

RESUMO

FMS-like tyrosine kinase 3 (FLT3) gene mutations have been found in more than one-third of Acute Myeloid Leukemia (AML) cases. The most common point mutation in FLT3 occurs at the 835th residue (D835A/E/F/G/H/I/N/V/Y), in the activation loop region. The D835 residue is critical in maintaining FLT3 inactive conformation; these mutations might influence the interaction with clinically approved AML inhibitors used to treat the AML. The molecular mechanism of each of these mutations and their interactions with AML inhibitors at the atomic level is still unknown. In this manuscript, we have investigated the structural consequence of native and mutant FLT-3 proteins and their molecular mechanisms at the atomic level, using molecular dynamics simulations (MDS). In addition, we use the molecular docking method to investigate the binding pattern between the FLT-3 protein and AML inhibitors upon mutations. This study apparently elucidates that, due to mutations in the D835, the FLT-3 structure loses its conformation and becomes more flexible compared to the native FLT3 protein. These structural changes are suggested to contribute to the relapse and resistance responses to AML inhibitors. Identifying the effects of FLT3 at the molecular level will aid in developing a personalized therapeutic strategy for treating patients with FLT-3-associated AML.


Assuntos
Leucemia Mieloide Aguda/genética , Tirosina Quinase 3 Semelhante a fms/genética , Simulação por Computador , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Mutação/efeitos dos fármacos , Mutação/genética , Mutação Puntual/efeitos dos fármacos , Mutação Puntual/genética , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética , Conformação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Tirosina Quinase 3 Semelhante a fms/metabolismo
20.
Nat Commun ; 12(1): 4130, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226546

RESUMO

Chromosomal translocations of the AF10 (or MLLT10) gene are frequently found in acute leukemias. Here, we show that the PZP domain of AF10 (AF10PZP), which is consistently impaired or deleted in leukemogenic AF10 translocations, plays a critical role in blocking malignant transformation. Incorporation of functional AF10PZP into the leukemogenic CALM-AF10 fusion prevents the transforming activity of the fusion in bone marrow-derived hematopoietic stem and progenitor cells in vitro and in vivo and abrogates CALM-AF10-mediated leukemogenesis in vivo. Crystallographic, biochemical and mutagenesis studies reveal that AF10PZP binds to the nucleosome core particle through multivalent contacts with the histone H3 tail and DNA and associates with chromatin in cells, colocalizing with active methylation marks and discriminating against the repressive H3K27me3 mark. AF10PZP promotes nuclear localization of CALM-AF10 and is required for association with chromatin. Our data indicate that the disruption of AF10PZP function in the CALM-AF10 fusion directly leads to transformation, whereas the inclusion of AF10PZP downregulates Hoxa genes and reverses cellular transformation. Our findings highlight the molecular mechanism by which AF10 targets chromatin and suggest a model for the AF10PZP-dependent CALM-AF10-mediated leukemogenesis.


Assuntos
Doença Aguda , Leucemia Mieloide Aguda/genética , Fatores de Transcrição/química , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Translocação Genética/genética , Animais , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Cromatina , Células HEK293 , Histonas/metabolismo , Humanos , Leucemia Mieloide Aguda/metabolismo , Metilação , Camundongos , Modelos Moleculares , Proteínas Monoméricas de Montagem de Clatrina/genética , Proteínas Monoméricas de Montagem de Clatrina/metabolismo , Nucleossomos , Conformação Proteica
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