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1.
BMC Cancer ; 22(1): 11, 2022 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-34979982

RESUMO

BACKGROUND: The mixed-lineage leukemia (MLL) gene is located on chromosome 11q23. The MLL gene can be rearranged to generate partial tandem duplications (MLL-PTD), which occurs in about 5-10% of acute myeloid leukemia (AML) with a normal karyotype and in 5-6% of myelodysplastic syndrome (MDS) patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently one of the curative therapies available for AML and MDS with excess blasts (MDS-EB). However, how the prognosis of patients with high levels of MLL-PTD after allo-HSCT, and whether MLL-PTD could be used as a reliable indicator for minimal residual disease (MRD) monitoring in transplant patients remains unknown. Our study purposed to analyze the dynamic changes of MLL-PTD peri-transplantation and the best threshold for predicting relapse after transplantation. METHODS: We retrospectively collected the clinical data of 48 patients with MLL-PTD AML or MDS-EB who underwent allo-HSCT in Peking University People's Hospital. The MLL-PTD was examined by real-time quantitative polymerase chain reaction (RQ-PCR) at the diagnosis, before transplantation and the fixed time points after transplantation. Detectable MLL-PTD/ABL > 0.08% was defined as MLL-PTD positive in this study. RESULTS: The 48 patients included 33 AML patients and 15 MDS-EB patients. The median follow-up time was 26(0.7-56) months after HSCT. In AML patients, 7 patients (21.2%) died of treatment-related mortality (TRM), 6 patients (18.2%) underwent hematological relapse and died ultimately. Of the 15 patients with MDS-EB, 2 patients (13.3%) died of infection. The 3-year cumulative incidence of relapse (CIR), overall survival (OS), disease-free survival (DFS) and TRM were 13.7 ± 5.2, 67.8 ± 6.9, 68.1 ± 6.8 and 20.3% ± 6.1%, respectively. ROC curve showed that post-transplant MLL-PTD ≥ 1.0% was the optimal cut-off value for predicting hematological relapse after allo-HSCT. There was statistical difference between post-transplant MLL-PTD ≥ 1.0% and MLL-PTD < 1.0% groups (3-year CIR: 75% ± 15.3% vs. 0%, P < 0.001; 3-year OS: 25.0 ± 15.3% vs. 80.7% ± 6.6%, P < 0.001; 3-year DFS: 25.0 ± 15.3% vs. 80.7 ± 6.6%, P < 0.001; 3-year TRM: 0 vs. 19.3 ± 6.6%, P = 0.277). However, whether MLL-PTD ≥ 1% or MLL-PTD < 1% before transplantation has no significant difference on the prognosis. CONCLUSIONS: Our study indicated that MLL-PTD had a certain stability and could effectively reflect the change of tumor burden. The expression level of MLL-PTD after transplantation can serve as an effective indicator for predicting relapse.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Proteína de Leucina Linfoide-Mieloide/genética , Recidiva Local de Neoplasia/genética , Proteínas de Fusão Oncogênica/genética , Intervalo Livre de Doença , Feminino , Seguimentos , Rearranjo Gênico/genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/cirurgia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/cirurgia , Recidiva Local de Neoplasia/mortalidade , Neoplasia Residual , Período Pós-Operatório , Valor Preditivo dos Testes , Prognóstico , Intervalo Livre de Progressão , Recidiva , Estudos Retrospectivos , Transplante Homólogo , Carga Tumoral/genética
2.
Front Immunol ; 12: 720354, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34539656

RESUMO

Gut acute graft-versus-host disease (aGVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with high mortality. Mucosa-associated invariant T (MAIT) cells are a group of innate-like T cells enriched in the intestine that can be activated by riboflavin metabolites from various microorganisms. However, little is known about the function or mechanism of action of MAIT cells in the occurrence of gut aGVHD in humans. In our study, multiparameter flow cytometry (FCM) was used to evaluate the number of MAIT cells and functional cytokines. 16S V34 region amplicon sequencing analysis was used to analyze the intestinal flora of transplant patients. In vitro stimulation and coculture assays were used to study the activation and function of MAIT cells. The number and distribution of MAIT cells in intestinal tissues were analyzed by immunofluorescence technology. Our study showed that the number and frequency of MAIT cells in infused grafts in gut aGVHD patients were lower than those in no-gut aGVHD patients. Recipients with a high number of MAITs in infused grafts had a higher abundance of intestinal flora in the early posttransplantation period (+14 days). At the onset of gut aGVHD, the number of MAIT cells decreased in peripheral blood, and the activation marker CD69, chemokine receptors CXCR3 and CXCR4, and transcription factors Rorγt and T-bet tended to increase. Furthermore, when gut aGVHD occurred, the proportion of MAIT17 was higher than that of MAIT1. The abundance of intestinal flora with non-riboflavin metabolic pathways tended to increase in gut aGVHD patients. MAIT cells secreted more granzyme B, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ under the interleukin (IL)-12/IL-18 stimulation [non-T-cell receptor (TCR) signal] and secreted most of the IL-17 under the cluster of differentiation (CD)3/CD28 stimulation (TCR signal). MAIT cells inhibited the proliferation of CD4+ T cells in vitro. In conclusion, the lower number of MAIT cells in infused grafts was related to the higher incidence of gut aGVHD, and the number of MAIT cells in grafts may affect the composition of the intestinal flora of recipients early after transplantation. The flora of the riboflavin metabolism pathway activated MAIT cells and promoted the expression of intestinal protective factors to affect the occurrence of gut aGVHD in humans.


Assuntos
Suscetibilidade a Doenças , Gastroenteropatias/etiologia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas , Células T Invariantes Associadas à Mucosa/imunologia , Células T Invariantes Associadas à Mucosa/metabolismo , Adolescente , Adulto , Biomarcadores , Citocinas/metabolismo , Disbiose , Feminino , Gastroenteropatias/diagnóstico , Gastroenteropatias/metabolismo , Gastroenteropatias/terapia , Microbioma Gastrointestinal/imunologia , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunomodulação , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Transdução de Sinais , Transplante Homólogo/efeitos adversos , Adulto Jovem
3.
Medicine (Baltimore) ; 99(50): e23569, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33327316

RESUMO

The SET nuclear proto-oncogene (SET)-nucleoporin (NUP) 214 fusion gene (SET-NUP214) is a rare leukemia fusion gene. Due to the limited number of samples with SET-NUP214 fusion gene in previous studies, the significance of SET-NUP214 for measurable residual disease (MRD) monitoring in patients with acute leukemia (AL) is still unclear. Our study aimed to observe the dynamic changes in SET-NUP214 expression before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and analyzed whether SET-NUP214 could be used to evaluate MRD status. Our study included 24 AL patients who were newly diagnosed with SET-NUP214 fusion gene and they all received allo-HSCT. Their MRD was evaluated by monitoring SET-NUP214 fusion gene and leukemia-associated immunophenotype (LAIP). The median follow-up time was 501 days (56-2208 days). Of the enrolled patients, 6 (25%) patients died, including 3 (12.5%) patients died of leukemia relapse. Total 5 (20.8%) patients experienced hematological relapse at a median of 225 days (56-1057 days) post-transplantation. The SET-NUP214 median expression level at diagnosis was 405.1% (14.6%-1482.4%). SET-NUP214 gene expression generally became positive prior to flow cytometry results. In addition, the Kaplan-Meier survival curves analysis showed that those who had SET-NUP214 positive (SET-NUP214+) post-transplantation had a higher 2-year cumulative incidence of leukemia relapse (CIR) of 43.7 ±â€Š18.8% (P < .05). However, there was no significant difference between SET-NUP214 positive and SET-NUP214 negative patients with regard to their 2-year overall survival (OS) (82.5 ±â€Š11.3 vs 64.6 ±â€Š17.5%, respectively, P = .271). ROC curve analysis turned out that the area under the ROC curve (AUC) was 0.916 (95% CI: 0.784-1.0; P = .005). In conclusion, SET-NUP214 fusion gene determined by real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) could be used to evaluate MRD status after allo-HSCT. Patients with positive SET-NUP214 expression after transplantation will have a poor prognosis.


Assuntos
Proteínas de Ligação a DNA/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Chaperonas de Histonas/genética , Leucemia/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Fusão Oncogênica/genética , Adolescente , Adulto , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Estimativa de Kaplan-Meier , Leucemia/diagnóstico , Leucemia/mortalidade , Leucemia/terapia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Prognóstico , Curva ROC , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
4.
Ann Hematol ; 99(1): 73-82, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31768677

RESUMO

For acute myeloid leukemia (AML) with nucleophosmin 1 mutation (NPM1m), multiparameter flow cytometry (FCM) and real-time quantitative polymerase chain reaction (RQ-PCR) are used to monitor minimal residual disease (MRD). However, the results of the two methods are sometimes inconsistent. This study was designed to analyze how to address the discordant results of FCM and RQ-PCR in AML patients undergoing chemotherapy, especially when positive FCM (FCM+) and negative NPM1m (NPM1m-) results are detected in the same sample. Our study included 93 AML patients with NPM1m positive (NPM1m+) who received chemotherapy but did not undergo hematopoietic stem cell transplantation. We monitored NPM1m and leukemia-associated immunophenotypes (LAIPs) by RQ-PCR and FCM, respectively, to assess MRD after each chemotherapy course. After each course of chemotherapy, all patients were classified into four groups based on the results of FCM and RQ-PCR: both negative (group 1, FCM-NPM1m-), single positive (group 2, FCM-NPM1m+; group 3, FCM+NPM1m-), or both positive (group 4, FCM+NPM1m+). The results showed that there was not a significant difference in the 2-year cumulative incidence of relapse (CIR) after each course of chemotherapy between group 2 and group 3. Furthermore, patients in groups 2 and 3 had a lower 2-year CIR than those in group 4 and a significantly higher 2-year CIR than those in group 1 after the first two courses. The patients in group 4 had a significantly higher 2-year CIR than those in group 1 after the first two courses. These results suggested that in the MRD monitoring process of AML patients, when the results of FCM and RQ-PCR are inconsistent (especially when FCM is positive and NPM1m is negative), these single-positive results still have predictive significance for relapse.


Assuntos
Citometria de Fluxo , Leucemia Mieloide Aguda , Mutação , Proteínas de Neoplasias , Proteínas Nucleares , Reação em Cadeia da Polimerase em Tempo Real , Adolescente , Adulto , Idoso , Feminino , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/genética , Neoplasia Residual , Proteínas Nucleares/sangue , Proteínas Nucleares/genética , Valor Preditivo dos Testes , Estudos Retrospectivos
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