RESUMO
The MEF2D rearrangement is a recurrent chromosomal abnormality detected in approximately 2.4-5.3% of patients with acute B-cell lymphoblastic leukemia (B-ALL). Currently, MEF2D-rearranged B-ALL is not classified as an independent subtype in the WHO classification. Consequently, the clinical significance of MEF2D rearrangement in B-ALL remains largely unexplored. In this study, we retrospectively screened 260 B-ALL patients with RNA sequencing data collected between November 2018 and December 2022. Among these, 10 patients were identified with MEF2D rearrangements (4 with MEF2D::HNRNPUL1, 3 with MEF2D::BCL9, 1 with MEF2D::ARID1B, 1 with MEF2D::DAZAP1 and 1 with MEF2D::HNRNPM). Notably, HNRNPM and ARID1B are reported as MEF2D fusion partners for the first time. The patient with the MEF2D::HNRNPM fusion was resistant to chemotherapy and chimeric antigen receptor T-cell therapy and relapsed early after allogenic stem cell transplantation. The patient with MEF2D::ARID1B experienced early extramedullary relapse after diagnosis. All 10 patients achieved complete remission after induction chemotherapy. However, 9/10 (90%) of whom experienced relapse. Three of the 9 patients relapsed with aberrant expression of myeloid antigens. The median overall survival of these patients was only 11 months. This small cohort showed a high incidence of early relapse and short survival in patients with MEF2D rearrangements.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Leucemia Mieloide Aguda , Humanos , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Estudos Retrospectivos , Pontuação de Propensão , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteína 1 Parceira de Translocação de RUNX1RESUMO
Fms-like tyrosine kinase 3 (FLT3) is frequently mutated in haematological malignancies. Although canonical FLT3 mutations including internal tandem duplications (ITDs) and tyrosine kinase domains (TKDs) have been extensively studied, little is known about the clinical significance of non-canonical FLT3 mutations. Here, we first profiled the spectrum of FLT3 mutations in 869 consecutively newly diagnosed acute myeloid leukaemia (AML), myelodysplastic syndrome and acute lymphoblastic leukaemia patients. Our results showed four types of non-canonical FLT3 mutations depending on the affected protein structure: namely non-canonical point mutations (NCPMs) (19.2%), deletion (0.7%), frameshift (0.8%) and ITD outside the juxtamembrane domain (JMD) and TKD1 regions (0.5%). Furthermore, we found that the survival of patients with high-frequency (>1%) FLT3-NCPM in AML was comparable to those with canonical TKD. In vitro studies using seven representative FLT3-deletion or frameshift mutant constructs showed that the deletion mutants of TKD1 and the FLT3-ITD mutant of TKD2 had significantly higher kinase activity than wild-type FLT3, whereas the deletion mutants of JMD had phosphorylation levels comparable with wild-type FLT3. All tested deletion mutations and ITD were sensitive to AC220 and sorafenib. Collectively, these data enrich our understanding of FLT3 non-canonical mutations in haematological malignancies. Our results may also facilitate prognostic stratification and targeted therapy of AML with FLT3 non-canonical mutations.
Assuntos
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Humanos , Tirosina Quinase 3 Semelhante a fms/genética , Mutação , Leucemia Mieloide Aguda/genética , Mutação PuntualRESUMO
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype with a poor prognosis under conventional chemotherapy. Ph-like ALL has a similar gene expression profile to Philadelphia chromosome-positive (Ph+) ALL, but is highly heterogeneous in terms of genomic alterations. Approximately 10-20% of patients with Ph-like ALL harbor ABL class (e.g. ABL1, ABL2, PDGFRB, and CSF1R) rearrangements. Additional genes that form fusion genes with ABL class genes are still being researched. These aberrations result from rearrangements including chromosome translocations or deletions and may be targets of tyrosine kinase inhibitors (TKIs). However, due to the heterogeneity and rarity of each fusion gene in clinical practice, there is limited data on the efficacy of tyrosine kinase inhibitors. Here, we report three cases of Ph-like B-ALL with ABL1 rearrangements treated with the dasatinib backbone for the CNTRL::ABL1, LSM14A::ABL1, and FOXP1::ABL1 fusion genes. All three patients achieved rapid and profound remission with no significant adverse events. Our findings suggest that dasatinib is a potent TKI for the treatment of ABL1-rearranged Ph-like ALL and can be used as a first-line treatment option for such patients.
Assuntos
Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Dasatinibe/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Inibidores de Proteínas Quinases/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Repressoras/genética , Fatores de Transcrição ForkheadRESUMO
OBJECTIVE: To assess changes of nutritional status by comprehensive nutrition assessment including nutritional risk screening, dietary assessment, blood biochemical index, and body composition in acute leukemia patients who had undergone chemotherapy. METHODS: A total of 169 patients with acute leukemia treated at The First Affiliated Hospital of Soochow University from June 2018 to August 2019 were recruited for this study. Before and after chemotherapy, the NRS-2002 and PG-SGA scales, dietary intake, blood biochemical index and body composition were evaluated to compare the changes of nutritional status. RESULTS: NRS-2002 score and PG-SGA score after chemotherapy were significantly increased than those before chemotherapy (P<0.001). Many patients had insufficient nutritional intake during chemotherapy, and the dietary intake score of patients with induction chemotherapy was significantly lower than that of patients with consolidation chemotherapy (P=0.043). The results of multivariate analysis showed that induction chemotherapy was the independent risk factor for the increase of PG-SGA scores and the decrease of dietary intake (all P<0.05). After chemotherapy, the white blood cell count, hemoglobin, and platelet count were significantly decreased (P<0.001), the prealbumin was significantly increased (P<0.001), and the blood glucose was increased (P=0.04), but albumin was not significantly changed. The weight, body mass index, fat-free mass, skeletal muscle mass and intracellular water were all significantly decreased (P<0.001), and visceral fat area was increased significantly after chemotherapy (P<0.05), especially in newly-diagnosed acute lymphoblastic leukemia patients after the induction of chemotherapy. CONCLUSION: The nutritional status of patients with acute leukemia has undergone significant changes after chemotherapy. A single indicator has limited significance for nutritional status assessment. Comprehensive assessment of nutritional status by multiple tools is worthy of clinical application.
Assuntos
Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Humanos , Quimioterapia de Indução/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Avaliação Nutricional , Estado Nutricional , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológicoRESUMO
Acute myeloid leukemia (AML) with t(8;21) is categorized as favorable-risk AML, but KIT mutations show a significantly poor prognostic impact in such patients. Persistent vulnerability to relapse is a major challenge in the treatment of this subtype of patients. Venetoclax is a BCL-2 selective inhibitor. The venetoclax+HMA strategy is also a notable salvage regimen that achieves good clinical outcomes in the treatment of relapsed or refractory (R/R) AML. However, in our clinical practice, we found that disease progressed rapidly even after venetoclax+azacitidine (AZA) therapy in two relapsed t(8;21) AML patients with KIT mutations. We report for the first time the therapeutic potential of venetoclax+midostaurin as a new combination therapy for relapsed t(8;21) AMLs with KIT mutations showing resistance to venetoclax+AZA therapy. Our ex vivo study also showed that midostaurin alone could inhibit proliferation and induce apoptosis of Kasumi-1 cells (e.g. Midostaurin induced G2 phase cell arrest, down-regulated p-KIT and BCL-2, while Bax protein levels were up-regulated) and observed a synergistic anti effect when the two drugs were combined. Our study shows that the venetoclax+midostaurin regimen may be a promising treatment option for R/R t(8;21) AML with KIT mutations.
RESUMO
Chidamide, a selective histone deacetylase inhibitor, has antitumour effects. 5azacitidine (5AZA), a hypomethylating agent, is effective in treating acute myeloid leukaemia (AML) and myelodysplastic syndrome. However, to the best of our knowledge, the effect of chidamide and 5AZA on AML cell lines has not been fully investigated. In the present study, the antileukaemia activity of chidamide, alone and in combination with 5AZA, was assessed on different subtypes of AML cell lines (M1M5) and primary samples from several patients with AML in vitro. The results indicated that the proliferation of leukaemia cells was significantly and dosedependently inhibited by chidamide and 5AZA alone or in combination. The combination also had marked synergistic effects to induce apoptosis of AML cells. The apoptosis of leukaemia cells was induced via downregulation of BCL2 and myeloidcell leukemia 1 (MCL1) levels. Of note, chidamide also degraded the MCL1 protein in venetoclaxresistant U937 cells, in which the MCL1 protein is upregulated. In addition, chidamide was able to induce myeloid differentiation (with CD11b upregulation) of AML cell lines or monocytic/dendritic differentiation (with CD86 upregulation) of primary cultured cells from several patients with AML. Chidamide was also able to promote the differentiation of the venetoclaxresistant U937 cell line by upregulating CD11b expression. In conclusion, chidamide alone or combined with 5AZA may be an effective therapy for AML.
Assuntos
Aminopiridinas/farmacologia , Azacitidina/farmacologia , Benzamidas/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Antimetabólitos Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Sinergismo Farmacológico , Epigenômica , Humanos , Células U937 , Regulação para CimaRESUMO
The management of patients with relapsed or refractory (R/R) acute myeloid leukaemia (AML) remains a challenge with few reliably effective treatments. Chidamide, a new selective HDAC inhibitor, has demonstrated some effectiveness in AML patients. Herein, we reported three patients with R/R AML who were unresponsive to venetoclax plus azacitidine (VA) but were successfully treated with VA when chidamide was added to the regimen. MCL1 is one of the anti-apoptotic proteins. Chidamide targets the MCL1 protein, which may permit venetoclax resistance when upregulated. We determined MCL1 protein expression in different AML cell lines, and chidamide could downregulate MCL1 expression in venetoclax resistance AML cells. In general, our experience showed that the chidamide/VA combination could improve the condition of R/R AML patients who are resistant to VA. Formally evaluating this regimen in R/R AML patients may be meaningful.
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/genéticaAssuntos
Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Terapia de Salvação , Sulfonamidas , Linfócitos TRESUMO
OBJECTIVE: To analyze the effect of clinical features, routine laboratory examination and related gene mutation on the OS of patients with myelodysplastic syndrome (MDS) after hematopoietic stem cell transplantation (HSCT). METHODS: 121 patients diagnosed as MDS and underwent hematopoietic stem cell transplantation in the First Affiliated Hospital of Soochow University from October 2013 to August 2018 were selected. Basic information of the patients was collected, and blood cells, bone marrow blasts at initial diagnosis, chromosomal karyotypes and gene mutations of the patients were detected.The effect of different factors on overall survival (OS) was analyzed by statistical method. RESULTS: Kaplan-Meier univariate analysis shows that OS was significanly different among different age groups. The 3-year OS rate of patients aged 0-29 years was (83.3±7.7) %, the 3-year OS rate in patients aged 30-49 years was (58.1±7.7 %), and the 3-year OS rate of patients aged 50-69 years was (31.0±22.6) %, which was statistically different (Pï¼0.05) between different groups. There were also significant differences in OS among patients with different transplantation types. 3-year OS rate: HLA-matched sibling HSCTï¼unrelated HLA-matched HSCTï¼haploidentical HSCTï¼micro HSCT. The OS rate of patients with bone marrow blasts≥10% seems lower than blastsï¼10%, but there was no statistical difference.The 3-year OS rate of patients with chromosomal karyotype complex abnormality was (47.7±11.5) %, and that of patients without complex abnormality was (80±4.2) % which was statistical difference (Pï¼0.05). Patients with DNMT3A, NRAS, TP53 and GATA2 mutations had shorter OS time compared with patients without mutation of these genes, which shows statistically significant (Pï¼0.05). COX multivariate analysis showed that age, chromosome karyotype, DNMT3A, TET2, GATA2 and NRAS were the independent factors influencing OS of patients after HSCT, with statistically significant difference. CONCLUSION: age of patients, donor selection of HSCT, chromosome karyotype, DNMT3A, NRAS, TP53, GATA2 and TET2 gene mutations are all independent factors affecting the OS of patients after HSCT. Therefore, the assessment of the OS of MDS patients with transplantation requires comprehensive consideration.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Células-Tronco Hematopoéticas , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Irmãos , Análise de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are frequent in acute myeloid leukemia (AML) and have important prognostic and therapeutic implications. FLT3 aberrations have been detected in a smaller fraction of acute lymphoblastic leukemia (ALL), and their prognostic value is not well established. We therefore assessed the FLT3 mutation in Chinese adolescent and adult ALL patients. PATIENTS AND METHODS: We have examined a cohort of 117 Chinese de novo adolescent and adult ALL patients enrolled between June 2016 and June 2017 from the First Affiliated Hospital of Soochow University. Prognostic factors for the ALL patient population were estimated by the Cox regression method. FLT3 mutation was detected by PCR, and its clinical effect was assessed by Kaplan-Meier curves. Differences in FLT3 mutation rate between subgroups were tested by chi-square test. RESULTS: FLT3 mutations accounted for 6.8% (8/117) in our cohort, including 3 internal tandem duplications (2.6%) and 5 tyrosine kinase domains (4.3%, 3 D835Y mutations, 1 M664I mutation, and 1 I867S mutation), which had no clinical significance on either overall survival (OS) or event-free survival. Alterations in FLT3 occurred more often in early thymic precursor (ETP)-ALL compared to non-ETP T-cell acute lymphoblastic leukemia (P = .028). However, the age at onset (P = .004), initial platelet counts (P = .018), and transplantation status (P = .007) were independent prognostic factors of OS for ALL in multivariate analysis. CONCLUSION: The FLT3 mutation was not common in Chinese ALL patients. Age at onset, platelet counts, and transplantation status rather than the presence of the FLT3 mutation were independent prognostic variables for ALL on OS in our cohort. Despite our small sample size, ETP-ALL may indicate a comparable higher FLT3-mutant rate. Because ETP-ALL has been identified as high-risk subgroup, these data warrant clinical studies with the implementation of FLT3 inhibitors in addition to early allogeneic hematopoietic stem-cell transplantation for FLT3-mutant ETP-ALL.
Assuntos
Mutação de Sentido Incorreto , Leucemia-Linfoma Linfoblástico de Células Precursoras , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Adulto , Idoso , Substituição de Aminoácidos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Taxa de SobrevidaRESUMO
OBJECTIVE: To detect and analyze the mutation status of FANCJ gene in adult AML patients, so as to provide the basis for studying the mechanism of FANCJ driven AML and guiding the preventim and treatment of deseese. METHODS: The cDNAs were extracted and transeripted from bone marrow cells and normal skin cells in 222 newly diagnosed AML patients. The primers were designed for FANCJ gene coding region, the mutations of FANCJ gene coding region in AML patients as well as the mutations of FANCJ gene in mucous membrane epethelia in patients were detected by PCR and sanger seguencing; the evolutionary conservation of FANCJ mutation in different organisms was analyzed by NCBI Blast online bioinformaties software. RESULTS: The sequencing analysis showed that the mutations of FANCJ gene happened in 11 sites of FANCJ gene coding region, which were as followed: exon5:c.G430A:p.A144T, exon6:c.A587G:pN196S, exon9:c.C1255T:p.R419W, exon10:c.G1442A:p.G481D, exon11:c.C1609G:p.L537V, exon16:c.C2360T:p.P787L, exon17:c.C2440T:p.R814C, exon19:c.C2608T:pH870Y, exon19:c.A2686G:p.I896V, exon19:c.C2830G:p.Q944E, exon20:c.G3412A:p.D1138N. Among them, the repeatability existed in mutations of A144T, N196S, R814C, I896V and Q944E. Beside, the mutation sites of A144, R419, G381, L537, P787, H870, Q944 and D1138 were highly conserved in different organisms. CONCLUSION: Among 222 adult AML patients, the mutations of FANCJ gene have been found in 26 patients, moreover, the mutation sites are relatively conserved in different organisms, and possess important fanction. The results of this study provide the basis for exploring the mexhanism of FANCJ gene driven AML and for guiding the prevantion and treatment of AML.
Assuntos
Leucemia Mieloide Aguda , Adulto , Primers do DNA , Humanos , Mutação , Reação em Cadeia da Polimerase , PrognósticoRESUMO
BACKGROUND: FLT3 mutations have been well-studied in acute myeloid leukemia (AML), and the detection of the FLT3 gene has become a clinical routine. However, it has not been fully analyzed in other hematologic malignancies, such as myelodysplastic syndromes (MDS). MATERIALS AND METHODS: Between 2010 and 2016, 304 adult patients with de novo MDS had the FLT3 sequence tested on their bone marrow sample. With 279 patients who had follow-up information, we also analyzed the impact of clinical and laboratory characteristics as well as FLT3 mutation status and treatment on prognosis. RESULTS: We found that the transformation rate was 3 (42.9%) of 7 patients in the FLT3-ITD-positive group, compared with 31 (10.4%) of 297 among FLT3-ITD-negative patients (P = .033). The median progression-free survival of the FLT3-ITD mutated and wild-type groups were 43 days and 363.5 days, respectively (P < .0001). The median overall survival (OS) of the 2 groups were 218 days and 410.5 days, respectively (P < .0001). We also found that 5 factors had independent prognostic impact on OS: white blood cell counts, bone marrow blast percentage, cytogenetics, transplantation status, and FLT3-ITD mutation. Furthermore, compared with the transformation group, the non-progression group was younger (P = .034), with a lower platelet count (P = .022), a lower bone marrow blast percentage (P = .001), a lower FLT3-ITD incidence (P = .007), and a longer OS (P < .0001). CONCLUSIONS: When observed at the MDS stage, patients harboring FLT3-ITD mutations had higher AML transformation rate, quicker disease progression, and shorter survival than wild-type patients. Nevertheless, once the disease progressed to leukemia, the impact of FLT3-ITD mutations on prognosis was slight. In addition, the prognosis of secondary AML was very poor whether there was an FLT3-ITD mutation or not.
Assuntos
Síndromes Mielodisplásicas/genética , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Prognóstico , Taxa de Sobrevida , Adulto JovemAssuntos
Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Mutagênese Insercional , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/enzimologia , Masculino , Taxa de Sobrevida , Tirosina Quinase 3 Semelhante a fms/metabolismoRESUMO
FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in hematological malignancies. FLT3 internal tandem duplication (FLT3-ITD) mutations located in juxtamembrane domain (JMD) and tyrosine kinase domain 1 (TKD1) regions account for two-thirds of all FLT3 mutations. The outcome of patients remains unsatisfactory, with low survival rates. It is not yet known whether the different mutations within the FLT3 gene are all associated with patient outcome. In addition, the cause of FLT3-ITD in-frame duplication events remains unknown. Although there are some published studies investigating the FLT3-ITD mutation and its clinical implications in Chinese acute myeloid leukemia (AML) patients, sample sizes tend to be small and detailed molecular profiles of FLT3 mutations are lacking in these studies. In our study, 227 FLT3-ITD sequences were analyzed from 227 Chinese de novo AML patients. ITD were next classified into 3 types based on molecular profiles of insertion DNA sequences: DNA complete duplication (type I), DNA partial duplication (type II) and complete random sequence (type III). From the 154 patients, we confirmed that high ITD allelic ratio (≥.5) and allogeneic stem cell transplant treatment under CR1 are independent prognostic factors. We also presented evidence that ITD integration sites in the hinge region or beta1-sheet region are an unfavorable prognostic factor in adult AML patients with FLT3-ITD mutations. These findings may help to decipher the mechanisms of FLT3-ITD in-frame duplication events and stratify patients when considering different therapeutic combinations.
Assuntos
Leucemia Mieloide Aguda/terapia , Transplante de Células-Tronco/métodos , Sequências de Repetição em Tandem , Tirosina Quinase 3 Semelhante a fms/química , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , China , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional , Prognóstico , Domínios Proteicos , Indução de Remissão , Tamanho da Amostra , Análise de Sobrevida , Transplante Homólogo , Adulto JovemRESUMO
OBJECTIVE: Two distinct forms of FMS-like tyrosine kinase 3 (FLT3) mutations, internal tandem duplication (ITD) in the juxtamembrane domain and point mutation within the activation loop of the tyrosine kinase domain (TKD), have been identified in considerable number of patients with AML. This study was aimed to analyze the impacts of these mutations on clinical outcomes, and assess the efficacy of different therapeutic regimens (allo-HSCT, sorafenib, or conventional chemotherapy) for AML patients with FLT3 mutations after the standard induction therapy. MATERIALS AND METHODS: We analyzed DNA samples from 158 consecutive de novo AML patients (18-60 years, excluding APL) with FLT3 mutations between July 2010 and October 2015. RESULTS: We found that AML patients with FLT3-TKD mutations have more favorable clinical outcomes than those with FLT3-ITD mutations. We also found that allo-HSCT therapy subgroup achieved longer OS and RFS than non-allo-HSCT therapy subgroup for FLT3-ITD positive patients (p < 0.001, p = 0.071). However, compared with the clinical outcomes in non-primary refractory patients, sorafenib did not show an obvious beneficial effect for the primary refractory patients. Further study on a large scale is still recommended. CONCLUSIONS: FLT3-TKD-mutated AML patients have more favorable clinical outcomes than those with FLT3-ITD mutations. Allo-HSCT therapy subgroup achieved longer OS and RFS than non-allo-HSCT therapy subgroup for FLT3-ITD positive patients. Compared with the clinical outcomes in non-primary refractory patients, sorafenib did not show an obvious beneficial effect for the primary refractory patients.
Assuntos
Leucemia Mieloide/genética , Leucemia Mieloide/terapia , Mutação , Tirosina Quinase 3 Semelhante a fms/genética , Doença Aguda , Adulto , Povo Asiático/genética , China , Tratamento Farmacológico/métodos , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide/etnologia , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/genética , Sorafenibe , Sequências de Repetição em Tandem/genética , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To find out the distributed characteristics of KIR2DL1 alleles frequencies and the recognition HLA-C ligand in the Chinese Han population. METHODS: The 111 patients and 116 donors from CMDP were performed the KIR2DL1 high-resolution typing and KIR genotyping using sequence-based testing (SBT) and PCR-SSP methods. RESULTS: A total of 224 individuals with KIR2DL1 locus was predominantly observed and accounted for 98.68% (224/227). There were 3 different KIR2DL1 alleles, including KIR2DL1*00302, *00201 and *00401 alleles polymorphism. The most common phenotype observed were KIR2DL1*00302 (84.82%, 380/448), KIR2DL1*00201 (12.05%, 54/448) and KIR2DL1*00401(3.13%,14/448), present at allele genotype frequencies of 61.04%,6.22% and 1.58% respectively. The allele homozygotic types of KIR2DL1*00302 and KIR2DL1*00302 were the most frequent in 6 KIR2DL1 allele by high resolution typing. The allele heterozygous types of KIR2DL1*00302 and KIR2DL1*00401 presented statistically different in haplotypes A/A and B/x (P=0.001), and KIR2DL1*00401 lacked of all A/A haplotype. The KIR2DL1*00302 and KIR2DL1*00201 allele had significant positive associations between different KIR pairs of KIR2DS1, KIR2DL3, KIR2DS4 and KIR3DL1/S1 using linkage disequilibrium analysis (P<0.01), respectively. In the receptor-ligand of KIR/HLA model after allo-HSCT, KIR2DL1*00302 alleles correlated with their HLA-C2 group ligands. KIR2DL1*00302 and HLA-C*06:02 was the most common combination ligand model, but KIR2DL1*00302 and HLA-C*01:02 was the most frequent mismatch ligand model with the development of NK cell-induced alloreactivity, meanwhile there was statistically significant difference of frequency distribution (P<0.05). CONCLUSION: The KIR2DL1*00302 was the most frequent allele in Chinese Han population. The KIR2DL1 high resolution typing would be beneficial for predicting donor NK cells all activity after hematopoietic stem cell transplantation and selecting suitable donors.
Assuntos
Antígenos HLA-C/genética , Receptores KIR2DL1/genética , Alelos , Povo Asiático/genética , Frequência do Gene , Genótipo , Haplótipos , Teste de Histocompatibilidade , Humanos , Ligantes , Polimorfismo GenéticoRESUMO
BACKGROUND: Interactions of tumor cells with the microenvironment were deemed to promote the tumor invasion and metastasis. CXC chemokine receptor 4 (CXCR4) and extracellular matrix metalloproteinase inducer (EMMPRIN) had reported to participate in this process. However the roles of bone marrow microenvironment in leukemic infiltration were not well investigated. METHODS: A co-culture system between SHI-1 cells and bone marrow stromal cells (BMSCs) is used to simulate the interactions of leukemic cells with their microenvironment. The trans-matrigel invasion was used to detect the capability of SHI-1 cells invasion. The BMSCs and SHI-1 cells were mixed in a ratio of 1:10 and added to the millicell chamber coated with matrigel. Either the co-culture supernatant or the functional blocking peptide of CXCR4 and EMMPRIN were added to the trans-matrigel invasion system. The expressions of EMMPRIN in SHI-1 cells and BMSCs were detected by RT-PCR. The changes of the expression of matrix metalloproteinase-2, 9 (MMP-2, MMP-9), tissue inhibitor of metalloproteinase 2 (TIMP-2), and CXCR4 mRNA in SHI-1 cells were determined by real-time PCR. The concentration of stromal cell derived factor 1 (SDF-1) in serum free supernatant was measured by ELISA. RESULTS: Both SHI-1 cells and BMSCs express EMMPRIN. SHI-1 cells could hardly invade the matrigel membrane; the coculture supernatant did not induce the invasion of SHI-1 cells. When contacting directly with BMSCs, SHI-1 cells invaded to the lower chamber of millicell were significantly increased. The functional blocking peptide of CXCR4 and EMMPRIN could significantly inhibit the invasion triggered by BMSCs. When co-culturing with BMSCs, the expression of CXCR4, MMP-2, MMP-9 and TIMP-2 mRNA in SHI-1 cells were significantly elevated in company with a significantly higher level of SDF-1 in the co-cultured serum-free supernatant. CONCLUSION: The interactions of leukemic cells and BMSCs play important roles in leukemic cell infiltration.
Assuntos
Comunicação Celular , Leucemia Monocítica Aguda/patologia , Células-Tronco Mesenquimais/fisiologia , Basigina/fisiologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Humanos , Invasividade Neoplásica , Receptores CXCR4/fisiologiaRESUMO
OBJECTIVE: To identify the distribution and differentiation of ABL kinase domain mutation in the Chinese Han nationality imatinib resistant chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL). METHODS: Bone marrow or peripheral blood samples of 112 imatinib resistant CML patients and 21 Ph(+)ALL patients were obtained from the first affiliated hospital of Soochow university according to local law. Total RNA was extracted from the mononuclear cells using a TRIzol reagent. ABL kinase domain (KD) mutation was detected by direct sequencing. RESULTS: Of the 112 imatinib resistant CML patients, 54.46%(61 cases) had ABL KD mutation. Twenty-three mutants were identified in 20 amino acid sites and 23.21% (26 cases) ABL KD mutations were in P-loop region. ABL KD mutations were also detected in 71.43% (15 cases) imatinib resistant Ph(+)ALL patients, with 10 mutations in 8 amino acid sites. The most frequent mutation was T315I (28.57%), followed by E255K/V (19.05%) and Y253F/H (14.29%). The frequency of T315I was much higher in imatinib resistant Ph(+) ALL than that in imatinib resistant CML (P = 0.001). Ph(+)ALL with additional chromosomal aberrations also had a higher rate of ABL KD mutation than that of CML (P = 0.010). Ph(+)ALL gained ABL KD mutation faster than CML (P < 0.010). CONCLUSION: Chinese imatinib resistant CML and Ph(+)ALL patients had different characteristics in ABL KD mutation. The rate of ABL KD mutation in Ph(+)ALL with additional chromosomal aberrations was much higher than that of CML with additional chromosomal aberrations.