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The clinical outcomes and genomic features of E2A-PBX1 (TCF3-PBX1)-positive B-cell acute lymphoblastic leukemia (B-ALL) patients remain unclear. A total of 137 patients carrying E2A-PBX1 among 3164 B-ALL patients between 2009 and 2019 were retrospectively analyzed. The 5-year overall survival (OS) and disease-free survival (DFS) rates of the whole cohort were 68.6% and 61.0%, respectively. Age [DFS, p = 0.037; cumulative incidence of relapse (CIR), p = 0.005] and the level of minimal residual disease (MRD) after induction chemotherapy (OS, p = 0.020; DFS, p = 0.002; CIR, p = 0.006) were independent risk factors. In adolescents/adults, allogeneic hematopoietic stem cell transplantation (allo-HSCT) at first complete remission (CR1) significantly improved the 5-year prognosis (OS, p < 0.001; DFS, p < 0.001; CIR, p < 0.001). Haploidentical HSCT decreased the CIR compared with human leukocyte antigen-matched HSCT in adolescents/adults (p = 0.017). Mutations in PBX1, PAX5, CTCF and SETD2, amplification of AKT3, and deletion of CDKN2A/B were common in the total cohort, while transcriptome differences were found in the cell cycle, nerve growth factor (NGF) signaling pathway and transcriptional regulation by TP53 between adolescents/adults and children. Patients with multiple subclones at diagnosis tended to have unfavorable 3-year prognoses (DFS, p = 0.010; CIR, p = 0.021). Leukemia clones with DNA repair gene mutations showed aggressive and treatment-refractory phenotypes in this subtype of ALL. Our study indicated that age, the level of MRD and DNA repair gene mutations were associated with E2A-PBX1-positive B-ALL outcomes. Allo-HSCT, especially haploidentical HSCT, could improve the prognosis of adolescent/adult patients.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Homeodomínio/genética , Proteínas de Fusão Oncogênica/genética , Fator de Transcrição 1 de Leucemia de Células Pré-B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Evolução Clonal , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoterapia Adotiva , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudos Retrospectivos , Análise de Sobrevida , Transcriptoma , Adulto JovemRESUMO
Neutropenic patients with hematological diseases are prone to severe infections. Granulocyte transfusion therapy (GTX) is considered as a logical therapeutic approach for these problems. However, the efficacy and complications of GTX have not been well identified. We retrospectively analyzed the clinical outcomes of GTX therapy in our hospital from 2009 to 2015. After 117 granulocyte transfusions for 47 patients, 72.3% of these patients' infections were effectively improved, and the overall survival rates at 30 and 120 days were 66.0 and 57.5%, respectively. The patients who experienced neutrophil recovery within 10 days after their therapy initiation had a better response and long-term survival period (14/15, 93.3%, vs 20/32, 62.5%, P = 0.037). Higher-dose granulocytes (> 2.55 × 108/kg) might improve the effective rate of infection in the patients who had more than 10 days neutrophil recovery time (17/23, 73.9%, vs 3/9, 33.3%, P = 0.049). In addition, GTX benefited the patients who suffered from pulmonary bacterial infections (16/20, 80%) compared with the bloodstream infection group (7/12, 58.3%) and skin or mucous infection group (1/5, 20%). The primary data showed that GTX did not affect the incidence of graft-versus-host disease (GVHD) and cytomegalovirus viremia when patients received further HSCT treatment. Collectively, GTX was an adjunct treatment modality for severely neutropenic patients who were likely to experience hematopoietic recovery. More randomized trials are needed to verify the efficacy and complications of GTX therapy.
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Transfusão de Leucócitos , Neutropenia/terapia , Pneumonia Bacteriana/terapia , Dermatopatias Bacterianas/terapia , Adolescente , Adulto , Idoso , Criança , Intervalo Livre de Doença , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Neutropenia/sangue , Neutropenia/complicações , Neutropenia/microbiologia , Pneumonia Bacteriana/sangue , Pneumonia Bacteriana/etiologia , Pneumonia Bacteriana/microbiologia , Estudos Retrospectivos , Dermatopatias Bacterianas/sangue , Dermatopatias Bacterianas/etiologia , Dermatopatias Bacterianas/microbiologia , Taxa de SobrevidaRESUMO
The receptor-interacting kinase-3 (RIP3) and its downstream substrate mixed lineage kinase domain-like protein (MLKL) have emerged as the key cellular components in programmed necrotic cell death. Receptors for the cytokines of tumor necrosis factor (TNF) family and Toll-like receptors (TLR) 3 and 4 are able to activate RIP3 through receptor-interacting kinase-1 and Toll/IL-1 receptor domain-containing adapter inducing IFN-ß, respectively. This form of cell death has been implicated in the host-defense system. However, the molecular mechanisms that drive the activation of RIP3 by a variety of pathogens, other than the above-mentioned receptors, are largely unknown. Here, we report that human herpes simplex virus 1 (HSV-1) infection triggers RIP3-dependent necrosis. This process requires MLKL but is independent of TNF receptor, TLR3, cylindromatosis, and host RIP homotypic interaction motif-containing protein DNA-dependent activator of IFN regulatory factor. After HSV-1 infection, the viral ribonucleotide reductase large subunit (ICP6) interacts with RIP3. The formation of the ICP6-RIP3 complex requires the RHIM domains of both proteins. An HSV-1 ICP6 deletion mutant failed to cause effective necrosis of HSV-1-infected cells. Furthermore, ectopic expression of ICP6, but not RHIM mutant ICP6, directly activated RIP3/MLKL-mediated necrosis. Mice lacking RIP3 exhibited severely impaired control of HSV-1 replication and pathogenesis. Therefore, this study reveals a previously uncharacterized host antipathogen mechanism.
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Interações Hospedeiro-Patógeno/imunologia , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteínas Virais/metabolismo , Animais , Cisteína Endopeptidases/metabolismo , Enzima Desubiquitinante CYLD , Ativação Enzimática , Glicoproteínas/metabolismo , Herpes Simples/imunologia , Herpes Simples/patologia , Herpes Simples/virologia , Herpesvirus Humano 1/patogenicidade , Humanos , Masculino , Camundongos , NF-kappa B/metabolismo , Necrose , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas de Ligação a RNA , Proteína Serina-Treonina Quinases de Interação com Receptores/química , Receptores do Fator de Necrose Tumoral/metabolismo , Receptor 3 Toll-Like/metabolismo , Proteínas Virais/química , Internalização do Vírus , Replicação ViralRESUMO
Coinfusion of unrelated cord blood (UCB) units in haploidentical hematopoietic cell transplantation (haplo-HCT) (haplo-cord HCT) for hematopoietic malignancies showed promising results in previous reports, but the efficiency of haplo-cord HCT in acute myeloid leukemia (AML) still lacks sufficient evidence. This multicenter, randomized, phase 3 trial (ClinicalTrials.gov NCT03719534) aimed to assess the efficacy and safety of haplo-cord HCT in AML patients. A total of 268 eligible patients aged 18-60 years, diagnosed with measurable residual disease in AML (excluding acute promyelocytic leukemia), with available haploidentical donors and suitable for allotransplantation, were randomly allocated (1:1) to receive haplo-cord HCT (n = 134) or haplo-HCT (n = 134). The 3-year overall survival (OS) was the primary endpoint in this study. Overall median follow-up was 36.50 months (IQR 24.75-46.50). The 3-year OS of Haplo-cord HCT group was better than haplo-HCT group (80.5%, 95% confidence interval [CI]: 73.7-87.9 vs. 67.8% 95% CI 60.0-76.5, p = 0.013). Favorable progression-free survival (70.3%, 95% CI 62.6-78.8 vs. 57.6%, 95% CI 49.6-67.0, p = 0.012) and cumulative incidence of relapse (12.1%, 95% CI 12.0-12.2 vs. 30.3%, 95% CI 30.1-30.4, p = 0.024) were observed in haplo-cord HCT group. Grade 3-4 adverse events (AEs) within two years posttransplantation in the two groups were similar. Haplo-cord HCT patients exhibited a faster cumulative incidence of neutrophil recovery (p = 0.026) and increased T-cell reconstitution in the early period posttransplantation. Haplo-cord HCT can improve OS in AML patients without excessive AEs, which may exert additional benefits for recipients of haplo-HCT.
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Transplante de Células-Tronco de Sangue do Cordão Umbilical , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Adulto , Leucemia Mieloide Aguda/terapia , Masculino , Feminino , Pessoa de Meia-Idade , Adolescente , Transplante Haploidêntico/efeitos adversos , Adulto JovemRESUMO
Chimeric antigen receptor-modified T cell (CAR-T) therapy is a promising novel immunotherapy for hematologic malignancies, and the diagnosis of infection after CAR-T infusion (CTI) presents challenges for clinicians. Plasma metagenomic next-generation sequencing (mNGS) has been shown to be a reliable diagnostic approach for infection, especially in immunocompromised patients. We aimed to investigate the diagnostic performance of plasma mNGS for infection in the first 30 days after CTI. A cohort of 153 patients who experienced a total of 170 febrile events during the first 30 days post-CTI were enrolled. Of these events, 51 were evaluated with both mNGS and CDM and 119 were assessed by conventional detection methods (CDM) only. We also explored the epidemiology of infections and differences in infection complications in cases with severe (>2) and moderate (≤2) cytokine release syndrome (CRS). Cases with febrile events were clinically divided into an infection group (IG) (95 of 170; 55.9%) and a noninfection group (NIG) (75 of 170; 44.1%). The sensitivity and specificity of mNGS for the diagnosis of infectious complications in the first 30 days after CTI were 69.2% and 89.2%, respectively, with the sensitivity superior to that of culture (P < .001). More infection cases assessed with both mNGS and CDM than those assessed with CDM only were laboratory-confirmed (63.9% versus 11.9%; P < .001). The serum C-reactive protein level was higher and the IFN-γ level was lower in the IG group, particularly in cases with CRS grade ≤2. Infection is a common complication in the first 30 days after CTI. The addition of mNGS to CDM improved the diagnostic yield, and mNGS showed relatively high sensitivity and specificity in post-CAR-T therapy febrile events.
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Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/efeitos adversos , Sequenciamento de Nucleotídeos em Larga Escala , Imunoterapia , Síndrome da Liberação de Citocina , Febre/diagnóstico , Febre/etiologiaRESUMO
We retrospectively explored the prognostic impact of DAT mutations at diagnosis in 122 RUNX1mut AML patients. RUNX1 missense mutation was dominant in the RUNT domain, and frameshift mutation was dominant in the TAD domain. DAT mutations occurred in 38.5% of RUNX1mut AML. After propensity score matching, DATpos patients had worse two-year relapse-free survival (RFS) than DATneg patients (p = .041). Moreover, RUNX1high (VAF ≥ 37.6%) patients showed poorer two-year overall survival (OS) and RFS than RUNX1low (VAF < 37.6%) patients (OS, p = .033; RFS, p = .027), especially in the RUNX1highDATpos group. Additionally, multivariate analysis confirmed that DAT mutations at diagnosis were an independent adverse factor for RFS. There were no significant differences in two-year OS and RFS between DATpos and DATneg patients or between RUNX1high and RUNX1low patients who undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Collectively, DAT mutations at diagnosis were adverse factors for RFS, and allo-HSCT could likely improve the poor outcomes of these patients.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Estudos Retrospectivos , Nucleofosmina , Mutação , Prognóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapiaRESUMO
Clinical outcomes of hematopoietic stem cell transplantation (HSCT) using a haploidentical stem cell graft and an unrelated umbilical cord blood unit (haplo-cord HSCT) for the treatment of B cell acute lymphoblastic leukemia (B-ALL) remain unclear. This study was conducted to explore the clinical outcomes of haplo-cord HSCT in patients with B-ALL. A total of 112 B-ALL patients who underwent haplo-cord HSCT and 64 B-ALL patients who underwent haploidentical HSCT (haplo-HSCT) at our center between 2010 and 2020 were retrospectively included in this study, and clinical outcomes and prognostic factors were further analyzed. Of the 112 haplo-cord HSCT recipients, 106 (94.6%) achieved complete haploidentical chimerism and 6 (5.4%) had mixed cord blood chimerism. No differences in neutrophil and platelet recovery or in the incidences of graft-versus-host disease, cytomegalovirus/Epstein-Barr virus viremia, bloodstream infection, or hemorrhagic cystitis were observed between the haplo-cord HSCT and haplo-HSCT groups. Compared with the haplo-HSCT group, the haplo-cord HSCT group had a higher absolute number of CD3+ cells (P = .029) and a lower ratio of CD3+CD4+ /CD3+CD8+ cells (P = .049) at 1 month post-transplantation. Moreover, the haplo-cord HSCT group had lower minimal residual disease (MRD) levels at 1 month (P = .020) and 100 days (P = .038) post-transplantation and a better 3-year prognosis (overall survival, P = .016; disease-free survival, P = .041; cumulative incidence of relapse [CIR], P = .016). The CIRs in patients with adverse genomic features (P = .040) or flow cytometry-based MRD (FCM-MRD) ≥1 × 10-4 (P = .033) were improved by haplo-cord HSCT. Multivariate analysis revealed that haplo-cord HSCT could independently improve the 3-year OS, DFS, and CIR of B-ALL patients (OS, P = .029; DFS, P = .024; CIR, P = .024). In addition, allo-HSCT at first complete remission was an independent parameter associated with 3-year OS for B-ALL patients (P = .014). An FCM-MRD ≥1 × 10-4 pre-HSCT could independently predict unfavorable 3-year DFS and CIR (DFS, P = .020; CIR, P = .036) in B-ALL patients. Our data suggest that the use of haplo-cord HSCT can independently improve survival in patients with B-ALL.
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Linfoma de Burkitt , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Infecções por Vírus Epstein-Barr , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Linfoma de Burkitt/etiologia , Infecções por Vírus Epstein-Barr/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 4 , Humanos , Neoplasia Residual/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Estudos RetrospectivosRESUMO
Background: Recent studies have highlighted the critical role of lysophosphatidylcholine acyltransferase 3 (LPCAT3) during cancer development. However, the abnormal expression and prognostic significance of pan-cancer have not been determined. Methods: We explored the expression level and prognostic value of LPCAT3 in 33 cancers by bioinformatics techniques, and comprehensively studied the biological function and immune infiltration based on the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases as well as many online websites. Results: LPCAT3 is significantly upregulated in many cancers, and it is associated with prognosis. Pan-cancer Cox regression analysis indicated that the high expression of LPCAT3 was associated with poor prognosis in acute myeloid leukemia (AML), lower-grade glioma (LGG), ovarian cancer (OV), and uveal melanoma (UVM), while better prognosis in kidney renal clear cell carcinoma (KIRC) (all P<0.05). Further analysis indicated that higher LPCAT3 expression in most cancers markedly decreased the infiltration of immune cells, except diffuse large B-cell lymphoma (DLBC), AML, LGG, stomach adenocarcinoma (STAD), and UVM. In contrast, the expression level of LPCAT3 was positively correlated with most immune checkpoints in colon adenocarcinoma (COAD), DLBC, LGG, liver hepatocellular carcinoma (LIHC), and UVM. Additionally, LPCAT3 expression was associated with tumor mutational burden (TMB) in 4 cancer types, while microsatellite instability (MSI) was in 3 cancer types. Functional enrichment analysis showed LPCAT3 upregulation was highly associated with lipid metabolism and ferroptosis processes. In addition, the result of prediction drug response suggested that B-cell lymphoma 2 (BCL2) inhibitors and Midostaurin may be a potential treatment option for AML with low-LPCAT3 expression. Conclusions: LPCAT3 expression is increased in multiple cancers. Overexpression of LPCAT3 is associated with poor prognosis and tumor immune microenvironment in many cancers, especially in AML. Our results showed that the oncogene of LPCAT3 may serve as a potential prognostic biomarker and/or therapeutic target in AML patients.
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Acute myeloid leukemia (AML) is an aggressive hematological malignancy that recurs in approximately 50% of cases. Elevated homing and uncontrolled expansion are characteristics of AML cells. Here, we identified that Fifth Ewing Variant (FEV) regulates the homing and expansion of AML cells. We found that FEV was re-expressed in 30% of primary AML samples and in almost all relapsed AML samples, and FEV expression levels were significantly higher in relapsed samples compared to primary samples. Interference of FEV expression in AML cell lines delayed leukemic progression and suppressed homing and proliferation. Moreover, FEV directly activated integrin subunit alpha 4 (ITGA4) transcription in a dose-dependent manner. Inhibition of integrin α4 activity with natalizumab (NZM) reduced the migration and colony-forming abilities of blasts and leukemic-initiating cells (LICs) in both primary and relapsed AML. Thus, our study suggested that FEV maintains the homing and expansion of AML cells by activating ITGA4 transcription and that targeting ITGA4 inhibits the colony-forming and migration capacities of blasts and LICs. Thus, these findings suggested that the FEV-ITGA4 axis may be a therapeutic target for both primary and relapsed AML.
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Early T-cell precursor (ETP) lymphoblastic leukemia/lymphoma is a high-risk T lymphoblastic leukemia/lymphoma (T-ALL/LBL) subgroup. We performed a real-world multicenter study to explore the clinical characteristics and prognosis of adolescent and young adults (AYA) and older adult ETP leukemia/lymphoma. A total of 103 patients with ETP-ALL/LBL in five centers in China between January 2016 and February 2021 were included in this study. The median age was 29 years (range, 15-70 years). Next-generation sequencing was performed in 94 patients and revealed that NOTCH1 (35.1%, 33 cases) was the most frequently mutated gene, followed by JAK3 (16.0%, 15 cases), PHF6 (13.80%, 13 cases) and EZH2 (11.70%, 11 cases). Complete remission (CR) was obtained in 74.2% (72/97) of patients, and 6 relapsed/refractory patients received a decitabine combined with AAG priming regimen as reinduction therapy with a CR rate of 50%. With a median follow-up of 18 months (0.5-60 months), the 2-year overall survival (OS) and relapse-free survival (RFS) rates for the entire cohort were 54% and 57.7%, respectively. Allogeneic stem cell transplantation (allo-SCT) was performed in 59.8% (58/97) of patients. After landmark analysis at 6 months, the 2-year OS rates was 77% of patients with allo-SCT at CR1 and 25% of patients with chemotherapy alone (p < 0.001). A multivariate analysis suggested that allo-SCT and CR after the first course induction were independent prognostic factors for OS. Collectively, we reported the largest cohort study with AYA and older adult ETP-ALL/LBL, and we found that ETP-ALL/LBL was highly invasive and had a poor long-term prognosis. Allo-SCT could significantly improve ETP-ALL/LBL patient survival.
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The role of MRD-directed risk stratification strategy for core binding factor acute myeloid leukemia (CBF-AML) patients with favorable risk genetics is still unknown. We retrospectively analyzed the clinical outcomes of 148 pure CBF-AML patients with first complete remission including MRD positive (n = 69) and MRD negative (n = 79) after two courses of consolidation from January 2009 to December 2018 in our center. We found that MRD positive after 2 courses of consolidation significantly influenced OS (5-year: 59%), PFS (5-year: 36%) and CIR (5-year: 58%) in favorable-risk CBF-AML patients with CR1. It was worth noting that the MRD status after two courses of consolidation might be the best timing for treatment choice and allo-HSCT was a promising treatment for favorable-risk CBF-AML patients with MRD positive after the second consolidation.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Neoplasia Residual , Prognóstico , Estudos Retrospectivos , Transplante HomólogoRESUMO
It has been reported that B7H1 and B7H3 play a role in graft-versus-host disease (GVHD), the major cause of treatment-related mortality (TRM) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) patients; however, the prognostic value of these factors has not been defined. We retrospectively collected 64 haplo-HSCT patients in our hospital from 2013 to 2014, as well as 38 HLA-matched-HSCT patients during the same period as the control group. We analyzed B7H1, B7H3, PD1, soluble CD25, ST2 and TNFR1 at 0 day, + 7 days, + 14 days and + 28 days after HSCT. The + 7 days/+ 14 days B7H1/B7H3 and + 28 days ST2 serum levels were higher in patients with aGVHD who underwent haplo-HSCT. Moreover, + 7 days B7H1/B7H3 serum levels were predictive of grade III-IV aGVHD (B7H1: AUC = 0.830, P < 0.001; B7H3: AUC = 0.775, P = 0.001). Haplo-HSCT patients with higher + 7 days B7H1/B7H3 or + 28 days ST2 serum levels had poor GVHD-related mortality (GRM) (B7H1: P < 0.001; B7H3: P = 0.002; ST2: P = 0.047). Multivariate analysis revealed that the + 7 days B7H1 serum level (P = 0.041), as well as viral infection (P = 0.015) and donor age (P = 0.012), could independently predict GRM. Collectively, we found that + 7 days B7H1/B7H3 serum levels can predict grade III-IV aGVHD, while only the + 7 days B7H1 serum level, together with viral infection and donor age, could independently predict GRM in patients with haplo-HSCT.