RESUMEN
BACKGROUND: Acute graft-versus-host disease (aGVHD), which is mainly mediated by allogeneic T cells, is a decisive factor in the success of allogeneic hematopoietic stem cell transplantation (allo-HCT). Prophylaxis for aGVHD in clinical patients is unsatisfactory, and there is still a huge unmet need for novel approaches. Icariin (ICA) shows potent anti-inflammatory activity and suppresses T cell-mediated immune responses. Thus, ICA is a potential drug for the prevention of aGVHD. However, there is no data assessing the impact of ICA on aGVHD after allo-HCT. PURPOSE: This study aimed to investigate the protective effect of ICA against aGVHD and its mechanisms. Moreover, the impact of ICA on the graft-versus-leukemia (GVL) effect and engraftment of donor hematopoietic and immune cells were assessed. METHODS: Different murine models of allo-HCT were developed to study the influence of the ICA on GVHD and GVL effect. Flow cytometry was used to analyze the growth of leukemia cells, alterations in different immune cells, and apoptosis. Cell proliferation was determined using a CCK-8 assay. RNA sequencing and quantitative proteomic analysis were performed to elucidate the underlying mechanisms, which were further verified by polymerase chain reaction or functional experiments. RESULTS: Different concentrations of ICA exhibited opposite effects: low-concentration ICA promoted, while high concentrations suppressed the proliferation and function of T cells. A high dose of ICA administration during days +3 to +5 post-allo-HCT can alleviate murine aGVHD but does not affect the course of chronic GVHD (cGVHD), the GVL effect against both acute myeloid and lymphoblastic leukemia, or the recovery of donor hematological and immune cells. ICA extensively represses the expansion, function, and infiltration of donor alloreactive T cells, while preserving regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC). Quantitative proteomic analysis showed that downregulation of integrin-linked kinase (ILK) and lymphocyte cytosolic protein 2 (LCP2) expression was possibly associated with ICA-mediated aGVHD protective effects. Furthermore, an inhibitor of ILK, which can alleviate murine aGVHD administered early after allo-HCT. CONCLUSION: These findings suggest that the bioactivities of ICA are associated with its concentration and that ICA can effectively mitigate aGVHD without losing GVL activity or engraftment of donor hematopoietic and immune cells. Thus, ICA may be a promising drug for preventing aGVHD in clinical settings.
Asunto(s)
Flavonoides , Enfermedad Injerto contra Huésped , Efecto Injerto vs Leucemia , Trasplante de Células Madre Hematopoyéticas , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Enfermedad Injerto contra Huésped/prevención & control , Animales , Flavonoides/farmacología , Efecto Injerto vs Leucemia/efectos de los fármacos , Ratones , Trasplante Homólogo , Modelos Animales de Enfermedad , Masculino , Femenino , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacosRESUMEN
HLA-C*02 246 has one nucleotide change from HLA-C*02:02:02:01 at nucleotide 523 changing Arginine to Cysteine at residue 151.
Asunto(s)
Alelos , Secuencia de Bases , Exones , Antígenos HLA-C , Prueba de Histocompatibilidad , Humanos , Antígenos HLA-C/genética , Análisis de Secuencia de ADN/métodos , Alineación de Secuencia , Sustitución de Aminoácidos , CodónRESUMEN
HLA-A*11:463 has one nucleotide change from HLA-A*11:01:01:01 at nucleotide 508 changing Lysine (146) to Glutamine.
Asunto(s)
Antígenos HLA-A , Nucleótidos , Humanos , Masculino , Secuencia de Bases , Alelos , Antígenos HLA-A/genética , China , Padre , Análisis de Secuencia de ADNRESUMEN
INTRODUCTION: Acute myeloid leukemia (AML) with internal tandem duplication (ITD) mutations in Fms-like tyrosine kinase 3 (FLT3) has an unfavorable prognosis. Recently, using newly emerging inhibitors of FLT3 has led to improved outcomes of patients with FLT3-ITD mutations. However, drug resistance and relapse continue to be significant challenges in the treatment of patients with FLT3-ITD mutations. This study aimed to evaluate the anti-leukemic effects of shikonin (SHK) and its mechanisms of action against AML cells with FLT3-ITD mutations in vitro and in vivo. METHODS: The CCK-8 assay was used to analyze cell viability, and flow cytometry was used to detect cell apoptosis and differentiation. Western blotting and real-time polymerase chain reaction (RT-PCR) were used to examine the expression of certain proteins and genes. Leukemia mouse model was created to evaluate the anti-leukemia effect of SHK against FLT3-ITD mutated leukemia in vivo. RESULTS: After screening a series of leukemia cell lines, those with FLT3-ITD mutations were found to be more sensitive to SHK in terms of proliferation inhibition and apoptosis induction than those without FLT3-ITD mutations. SHK suppresses the expression and phosphorylation of FLT3 receptors and their downstream molecules. Inhibition of the NF-κB/miR-155 pathway is an important mechanism through which SHK kills FLT3-AML cells. Moreover, a low concentration of SHK promotes the differentiation of AML cells with FLT3-ITD mutations. Finally, SHK could significantly inhibit the growth of MV4-11 cells in leukemia bearing mice. CONCLUSION: The findings of this study indicate that SHK is a promising drug for the treatment of FLT3-ITD mutated AML.
RESUMEN
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell malignancy, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curable treatment. The outcomes after transplant are influenced by both disease characteristics and patient comorbidities. To develop a novel prognostic model to predict the post-transplant survival of CMML patients, we identified risk factors by applying univariable and multivariable Cox proportional hazards regression to a derivation cohort. In multivariable analysis, advanced age (hazard ratio [HR] 3.583), leukocyte count (HR 3.499), anemia (HR 3.439), bone marrow blast cell count (HR 2.095), and no chronic graft versus host disease (cGVHD; HR 4.799) were independently associated with worse survival. A novel prognostic model termed ABLAG (Age, Blast, Leukocyte, Anemia, cGVHD) was developed and the points were assigned according to the regression equation. The patients were categorized into low risk (0-1), intermediate risk (2, 3), and high risk (4-6) three groups and the 3-year overall survival (OS) were 93.3% (95%CI, 61%-99%), 78.9% (95%CI, 60%-90%), and 51.6% (95%CI, 32%-68%; p < .001), respectively. In internal and external validation cohort, the area under the receiver operating characteristic (ROC) curves of the ABLAG model were 0.829 (95% CI, 0.776-0.902) and 0.749 (95% CI, 0.684-0.854). Compared with existing models designed for the nontransplant setting, calibration plots, and decision curve analysis showed that the ABLAG model revealed a high consistency between predicted and observed outcomes and patients could benefit from this model. In conclusion, combining disease and patient characteristic, the ABLAG model provides better survival stratification for CMML patients receiving allo-HSCT.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mielomonocítica Crónica , Humanos , Pronóstico , Trasplante Homólogo/efectos adversos , Estudios Retrospectivos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/etiologíaRESUMEN
Relapsed or refractory (r/r) mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a poor prognosis. Bruton tyrosine kinase (BTK) is a mediator of B-cell receptor signaling and is associated with the development of B-cell lymphomas. Patients with r/r MCL were enrolled in this phase 1/2 study and treated with orelabrutinib, a novel, highly selective BTK inhibitor. The median number of prior regimens was 2 (range, 1-4). The median age was 62 years (range, 37-73 years). Eligible patients received oral orelabrutinib 150 mg once daily (n = 86) or 100 mg twice daily (n = 20) until disease progression or unacceptable toxicity. A dose of 150 mg once daily was chosen as the preferred recommended phase 2 dose. After a median follow-up duration of 23.8 months, the overall response rate was 81.1%, with 27.4% achieving a complete response and 53.8% achieving a partial response. The median duration of response and progression-free survival were 22.9 and 22.0 months, respectively. The median overall survival (OS) was not reached, and the rate of OS at 24 months was 74.3%. Adverse events (AEs) occurring in >20% of patients were thrombocytopenia (34.0%), upper respiratory tract infection (27.4%), and neutropenia (24.5%). Grade ≥3 AEs were infrequent and most commonly included thrombocytopenia (13.2%), neutropenia (8.5%), and anemia (7.5%). Three patients discontinued treatment because of treatment-related adverse events (TRAEs), but no fatal TRAEs were reported. Orelabrutinib showed substantial efficacy and was well tolerated in patients with r/r MCL. This trial was registered at www.clinicaltrials.gov as #NCT03494179.
Asunto(s)
Linfoma de Células del Manto , Neutropenia , Trombocitopenia , Adulto , Humanos , Persona de Mediana Edad , Linfoma de Células del Manto/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Neutropenia/inducido químicamente , Trombocitopenia/inducido químicamenteRESUMEN
HLA-C*01:02:86 has one synonymous nucleotide C > T change from HLA-C*01:02:01:01 at nucleotide 879 (residue 269 Proline).
Asunto(s)
Pueblos del Este de Asia , Antígenos HLA-C , Humanos , Secuencia de Bases , Antígenos HLA-C/genética , Alelos , Análisis de Secuencia de ADN , NucleótidosRESUMEN
Acute myeloid leukemia (AML) with retinoic acid receptor γ (RARG) rearrangement has clinical, morphologic, and immunophenotypic features similar to classic acute promyelocytic leukemia. However, AML with RARG rearrangement is insensitive to alltrans retinoic acid (ATRA) and arsenic trioxide (ATO) and carries a poor prognosis. We initiated a global cooperative study to define the clinicopathological features, genomic and transcriptomic landscape, and outcomes of AML with RARG rearrangements collected from 29 study groups/institutions worldwide. Thirty-four patients with AML with RARG rearrangements were identified. Bleeding or ecchymosis was present in 18 (54.5%) patients. Morphology diagnosed as M3 and M3v accounted for 73.5% and 26.5% of the cases, respectively. Immunophenotyping showed the following characteristics: positive for CD33, CD13, and MPO but negative for CD38, CD11b, CD34, and HLA-DR. Cytogenetics showed normal karyotype in 38% and t(11;12) in 26% of patients. The partner genes of RARG were diverse and included CPSF6, NUP98, HNRNPc, HNRNPm, PML, and NPM1. WT1- and NRAS/KRAS-mutations were common comutations. None of the 34 patients responded to ATRA and/or ATO. Death within 45 days from diagnosis occurred in 10 patients (â¼29%). At the last follow-up, 23 patients had died, and the estimated 2-year cumulative incidence of relapse, event-free survival, and overall survival were 68.7%, 26.7%, and 33.5%, respectively. Unsupervised hierarchical clustering using RNA sequencing data from 201 patients with AML showed that 81.8% of the RARG fusion samples clustered together, suggesting a new molecular subtype. RARG rearrangement is a novel entity of AML that confers a poor prognosis. This study is registered with the Chinese Clinical Trial Registry (ChiCTR2200055810).
Asunto(s)
Leucemia Mieloide Aguda , Leucemia Promielocítica Aguda , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Promielocítica Aguda/genética , Tretinoina , Antígenos HLA-DR , Trióxido de ArsénicoRESUMEN
Acute myeloid leukemia (AML) with NPM1 mutation is a distinct genetic entity with favorable outcomes. Nevertheless, emerging evidence suggests that NPM1-mutated AML is still a highly heterogeneous disorder. In this study, 266 patients with AML with NPM1 mutations were retrospectively analyzed to evaluate the associations between variant allele frequency (VAF) of NPM1 mutations, co-mutated genes, measurable residual disease (MRD), and patient outcomes. Multiparameter flow cytometry (MFC) and real-time quantitative polymerase chain reaction (RT-PCR) were used for monitoring MRD. Ultimately, 106 patients were included in the long-term follow-up period. Patients with high NPM1 VAF (≥ 42.43%) had poorer 2-year relapse-free survival (RFS) (55.7% vs. 70.2%, P = 0.017) and overall survival (OS) (63.7% vs. 82.0%, P = 0.027) than those with low VAF. DNMT3A mutations negatively influenced the outcomes of patients with NPM1 mutations. Patients with high DNMT3A VAF or NPM1/DNMT3A/FLT3-ITD triple mutations had shorter RFS and significantly lower OS than that in controls. After two cycles of chemotherapy, patients with positive MFC MRD results had lower RFS (MRD+ vs. MRD-:44.9% vs. 67.6%, P = 0.007) and OS (61.5% vs. 76.6%, P = 0.011) than those without positive MFC MRD results. In multivariate analysis, high NPM1 VAF (hazard ratio [HR] = 2.045; P = 0.034) and positive MRD after two cycles of chemotherapy (HR = 3.289; P = 0.003) were independent risk factors for RFS; MRD positivity after two cycles of chemotherapy (HR = 3.293; P = 0.008) independently predicted the OS of the patients. These results indicate that VAF of both NPM1 gene itself or certain co-occurring gene pre-treatment and MRD post-treatment are potential markers for restratifying the prognoses of patients AML having NPM1 mutations.
Asunto(s)
Leucemia Mieloide Aguda , Proteínas Nucleares , Humanos , Proteínas Nucleares/genética , Nucleofosmina , Estudios Retrospectivos , Citometría de Flujo , Pronóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Recurrencia , Mutación , Neoplasia Residual/genéticaRESUMEN
In recent decades, haploidentical stem cell transplantation (haplo-SCT) to treat severe aplastic anemia (SAA) has achieved remarkable progress. However, long-term results are still lacking. We conducted a multicenter prospective study involving SAA patients who underwent haplo-SCT as salvage therapy. Long-term outcomes were assessed, mainly focusing on survival and quality of life (QoL). Longitudinal QoL was prospectively evaluated during pretransplantation and at 3 and 5 years posttransplantation using the SF-36 scale in adults and the PedsQL 4.0 scale in children. A total of 287 SAA patients were enrolled, and the median follow-up was 4.56 years (range, 3.01-9.05 years) among surviving patients. During the long-term follow-up, 268 of 275 evaluable patients (97.5%) obtained sustained full donor chimerism, and 93.4% had complete hematopoietic recovery. The estimated overall survival and failure-free survival for the whole cohort at 9 years were 85.4% ± 2.1% and 84.0% ± 2.2%, respectively. Age (≥18 years) and a poorer performance status (ECOG >1) were identified as risk factors for survival outcomes. For QoL recovery after haplo-SCT, we found that QoL progressively improved from pretransplantation to the 3-year and 5-year time points with statistical significance. The occurrence of chronic graft versus host disease was a risk factor predicting poorer QoL scores in both the child and adult cohorts. At the last follow-up, 74.0% of children and 72.9% of adults returned to normal school or work. These inspiring long-term outcomes suggest that salvage transplantation with haploidentical donors can be routine practice for SAA patients without human leukocyte antigen (HLA)-matched donors.
Asunto(s)
Anemia Aplásica , Enfermedad Injerto contra Huésped , Niño , Adulto , Humanos , Adolescente , Trasplante Haploidéntico/métodos , Estudios de Seguimiento , Estudios Prospectivos , Calidad de Vida , Anemia Aplásica/terapia , Enfermedad Injerto contra Huésped/etiologíaRESUMEN
HLA-C*01:212 differs from HLA-C*01:02:01:01 by two non-synonmous nucleotide changes at positions 368 and 379 in exon 3.
Asunto(s)
Pueblo Asiatico , Antígenos HLA-C , Alelos , China , Exones/genética , Antígenos HLA-C/genética , Humanos , Análisis de Secuencia de ADNRESUMEN
HLA-B*13:157 has one nucleotide change from HLA-B*13:02:01:01 at nucleotide 323 changing Tyrosine to Phenylalanine at residue 84.
Asunto(s)
Antígenos HLA-B , Nucleótidos , Alelos , Secuencia de Bases , Antígenos HLA-B/genética , Prueba de Histocompatibilidad , Humanos , Análisis de Secuencia de ADNRESUMEN
HLA-C*15:244 has one nucleotide change from HLA-C*15:05:01:01 at nucleotide 308 changing Arginine to Glutamine at residue 79.
Asunto(s)
Genes MHC Clase I , Antígenos HLA-C , Alelos , Secuencia de Bases , Antígenos HLA-C/genética , Humanos , Nucleótidos , Análisis de Secuencia de ADNRESUMEN
HLA-B*35:251:02 has one nucleotide change from HLA-B*35:22:01:01 at nucleotide 363 changing Serine to Arginine at residue 97.
Asunto(s)
Genes MHC Clase I , Antígenos HLA-B , Alelos , Secuencia de Bases , Antígenos HLA-B/genética , Prueba de Histocompatibilidad , Humanos , Nucleótidos , Análisis de Secuencia de ADNRESUMEN
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a curative option for severe aplastic anemia (SAA), and transplantation from identical sibling donors (ISD) has been recommended as a first-line treatment. Haploidentical donor (HID) transplantation for SAA has made great advances; thus, an increased role of HID-SCT in SAA should be considered. We performed a national registry-based analysis comparing long-term outcomes in the upfront HID or upfront ISD SCT setting. A total of 342 SAA patients were enrolled, with 183 patients receiving HID SCT and 159 receiving ISD SCT. The estimated 9-year overall survival and failure-free survival were 87.1±2.5% and 89.3±3.7% (P=0.173) and 86.5±2.6% versus 88.1±3.8% (P=0.257) for patients in the HID and ISD SCT groups, respectively. Transplantation from HID or ISD SCT has greatly improved quality of life (QoL) levels post-HSCT compared to pre-HSCT. The occurrence of chronic graft-versus-host disease was the only identified adverse factor affecting each subscale of QoL. Physical and mental component summaries in adults as well as physical, mental, social, and role well-being in children were all similar between HID and ISD SCT at 5-year time points. At the last follow-up, the proportion of returning to society was comparable between the HID and ISD groups, showing 78.0% versus 84.6% among children and 74.6% versus 81.2% among adults. These data suggest that haploidentical transplant can be considered a potential therapeutic option in the upfront setting for SAA patients in the absence of an HLA-identical related or unrelated donor.
Asunto(s)
Anemia Aplásica , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Adulto , Niño , Humanos , Anemia Aplásica/terapia , Hermanos , Calidad de Vida , Enfermedad Injerto contra Huésped/etiología , Donante no Emparentado , Sistema de Registros , Acondicionamiento PretrasplanteRESUMEN
HLA-B*40:482 has one nucleotide change from HLA-B*40:06:01:01 at nucleotide 430 changing glycine to arginine at residue 120.
Asunto(s)
Antígenos HLA-B , Nucleótidos , Alelos , Secuencia de Bases , Antígenos HLA-B/genética , Humanos , Análisis de Secuencia de ADNRESUMEN
One nucleotide replacement at position 728 of HLA-A*02:07:01 results in a novel allele, HLA-A*02:981.
Asunto(s)
Antígenos HLA-A , Alelos , Antígenos HLA-A/genética , Humanos , Análisis de Secuencia de ADNRESUMEN
HLA-A*24:516 has one nucleotide change from HLA-A*24:02:01:01 at nucleotide 194 where Alanine (41) is changed to Glycine.
Asunto(s)
Antígenos HLA-A , Núcleo Familiar , Alelos , Secuencia de Bases , China , Exones/genética , Antígenos HLA-A/genética , Humanos , Nucleótidos , Análisis de Secuencia de ADNRESUMEN
HLA-A*11:398 has one nonsynonymous nucleotide change from HLA-A*11:01:01:01 at nucleotide 709, changing Isoleucine 213 to Valine.
Asunto(s)
Antígenos HLA-A , Nucleótidos , Alelos , Secuencia de Bases , China , Antígenos HLA-A/genética , Humanos , Análisis de Secuencia de ADNRESUMEN
Mutations in CCAAT enhancer binding protein A gene (CEBPA) are one of the common genetic alterations in acute myeloid leukemia (AML). Recently, the emergence of new evidence makes it necessary to reconsider the subsets and treatment of AML patients with CEBPA mutations. This review will summarize the history of research progress of CEBPA mutations in AML, the heterogeneities of AML with CEBPA double mutations (CEBPA dm), and two special subtypes of CEBPA mutated AML. We will discuss the treatment of AML with CEBPA mutations as well, and finally propose a new algorithm for the treatment of these patients, including both familial and sporadic CEBPA mutated AML patients. This review may be beneficial for further investigation and optimizing clinical management of AML patients with CEBPA mutations.