ABSTRACT
Therapy-related myeloid neoplasms (tMN) are complications of cytotoxic therapies. Risk of tMN is high in recipients of autologous hematopoietic stem cell transplantation (aHSCT). Acquisition of genomic mutations represents a key pathogenic driver but the origins, timing and dynamics, particularly in the context of preexisting or emergent clonal hematopoiesis (CH), have not been sufficiently clarified. We studied a cohort of 1507 patients undergoing aHSCT and a cohort of 263 patients who developed tMN without aHSCT to determine clinico-molecular features unique to post-aHSCT tMN. We show that tMN occurs in up to 2.3% of patients at median of 2.6 years post-AHSCT. Age ≥ 60 years, male sex, radiotherapy, high treatment burden ( ≥ 3 lines of chemotherapy), and graft cellularity increased the risk of tMN. Time to evolution and overall survival were shorter in post-aHSCT tMN vs. other tMN, and the earlier group's mutational pattern was enriched in PPM1D and TP53 lesions. Preexisting CH increased the risk of adverse outcomes including post-aHSCT tMN. Particularly, antecedent lesions affecting PPM1D and TP53 predicted tMN evolution post-transplant. Notably, CH-derived tMN had worse outcomes than non CH-derived tMN. As such, screening for CH before aHSCT may inform individual patients' prognostic outcomes and influence their prospective treatment plans. Presented in part as an oral abstract at the 2022 American Society of Hematology Annual Meeting, New Orleans, LA, 2022.
Subject(s)
Clonal Hematopoiesis , Hematopoietic Stem Cell Transplantation , Mutation , Neoplasms, Second Primary , Transplantation, Autologous , Humans , Hematopoietic Stem Cell Transplantation/adverse effects , Male , Middle Aged , Female , Transplantation, Autologous/adverse effects , Adult , Neoplasms, Second Primary/etiology , Neoplasms, Second Primary/genetics , Neoplasms, Second Primary/therapy , Aged , Prognosis , Myeloproliferative Disorders/therapy , Myeloproliferative Disorders/etiology , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/pathology , Young Adult , Adolescent , Protein Phosphatase 2C/genetics , Tumor Suppressor Protein p53/genetics , Follow-Up Studies , Lymphoma/therapy , Lymphoma/etiology , Lymphoma/genetics , Survival RateABSTRACT
INTRODUCTION: Circulating tumor DNA (ctDNA) is emerging as a promising, non-invasive diagnostic and surveillance biomarker in solid organ malignancy. However, its utility before and after liver transplant (LT) for patients with primary and secondary liver cancers is still underexplored. METHODS: Patients undergoing LT for hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and colorectal liver metastases (CRLM) with ctDNA testing were included. CtDNA testing was conducted pre-transplant, post-transplant, or both (sequential) from 11/2019 to 09/2023 using Guardant360, Guardant Reveal, and Guardant360 CDx. RESULTS: 21 patients with HCC (n = 9, 43%), CRLM (n = 8, 38%), CCA (n = 3, 14%), and mixed HCC/CCA (n = 1, 5%) were included in the study. The median follow-up time was 15 months (range: 1-124). The median time from pre-operative testing to surgery was 3 months (IQR: 1-4; range: 0-5), and from surgery to post-operative testing, it was 9 months (IQR: 2-22; range: 0.4-112). A total of 13 (62%) patients had pre-transplant testing, with 8 (62%) having ctDNA detected (ctDNA+) and 5 (32%) not having ctDNA detected (ctDNA-). A total of 18 (86%) patients had post-transplant testing, 11 (61%) of whom were ctDNA+ and 7 (33%) of whom were ctDNA-. The absolute recurrence rates were 50% (n = 5) in those who were ctDNA+ vs. 25% (n = 1) in those who were ctDNA- in the post-transplant setting, though this difference was not statistically significant (p = 0.367). Six (29%) patients (HCC = 3, CCA = 1, CRLM = 2) experienced recurrence with a median recurrence-free survival of 14 (IQR: 6-40) months. Four of these patients had positive post-transplant ctDNA collected following diagnosis of recurrence, while one patient had positive post-transplant ctDNA collected preceding recurrence. A total of 10 (48%) patients had sequential ctDNA testing, of whom n = 5 (50%) achieved ctDNA clearance (+/-). The remainder were ctDNA+/+ (n = 3, 30%), ctDNA-/- (n = 1, 10%), and ctDNA-/+ (n = 1, 11%). Three (30%) patients showed the acquisition of new genomic alterations following transplant, all without recurrence. Overall, the median tumor mutation burden (TMB) decreased from 1.23 mut/Mb pre-transplant to 0.00 mut/Mb post-transplant. CONCLUSIONS: Patients with ctDNA positivity experienced recurrence at a higher rate than the ctDNA- patients, indicating the potential role of ctDNA in predicting recurrence after curative-intent transplant. Based on sequential testing, LT has the potential to clear ctDNA, demonstrating the capability of LT in the treatment of systemic disease. Transplant providers should be aware of the potential of donor-derived cell-free DNA and improved approaches are necessary to address such concerns.
ABSTRACT
Hypomethylating agents (HMA) prolong survival and improve cytopenias in individuals with higher-risk myelodysplastic syndrome (MDS). Only 30-40% of patients, however, respond to HMAs, and responses may not occur for more than 6 months after HMA initiation. We developed a model to more rapidly assess HMA response by analyzing early changes in patients' blood counts. Three institutions' data were used to develop a model that assessed patients' response to therapy 90 days after the initiation using serial blood counts. The model was developed with a training cohort of 424 patients from 2 institutions and validated on an independent cohort of 90 patients. The final model achieved an area under the receiver operating characteristic curve (AUROC) of 0.79 in the train/test group and 0.84 in the validation group. The model provides cohort-wide and individual-level explanations for model predictions, and model certainty can be interrogated to gauge the reliability of a given prediction.
ABSTRACT
PURPOSE: Patients with myelodysplastic syndromes (MDS) have a survival that can range from months to decades. Prognostic systems that incorporate advanced analytics of clinical, pathologic, and molecular data have the potential to more accurately and dynamically predict survival in patients receiving various therapies. METHODS: A total of 1,471 MDS patients with comprehensively annotated clinical and molecular data were included in a training cohort and analyzed using machine learning techniques. A random survival algorithm was used to build a prognostic model, which was then validated in external cohorts. The accuracy of the proposed model, compared with other established models, was assessed using a concordance (c)index. RESULTS: The median age for the training cohort was 71 years. Commonly mutated genes included SF3B1, TET2, and ASXL1. The algorithm identified chromosomal karyotype, platelet, hemoglobin levels, bone marrow blast percentage, age, other clinical variables, seven discrete gene mutations, and mutation number as having prognostic impact on overall and leukemia-free survivals. The model was validated in an independent external cohort of 465 patients, a cohort of patients with MDS treated in a prospective clinical trial, a cohort of patients with paired samples at different time points during the disease course, and a cohort of patients who underwent hematopoietic stem-cell transplantation. CONCLUSION: A personalized prediction model on the basis of clinical and genomic data outperformed established prognostic models in MDS. The new model was dynamic, predicting survival and leukemia transformation probabilities at different time points that are unique for a given patient, and can upstage and downstage patients into more appropriate risk categories.
Subject(s)
Algorithms , Biomarkers, Tumor/genetics , Cell Transformation, Neoplastic/pathology , Hematopoietic Stem Cell Transplantation/mortality , Models, Statistical , Mutation , Myelodysplastic Syndromes/mortality , Adult , Aged , Aged, 80 and over , Cell Transformation, Neoplastic/genetics , Clinical Trials, Phase II as Topic , Disease Progression , Female , Follow-Up Studies , Genomics , Humans , Male , Middle Aged , Myelodysplastic Syndromes/pathology , Myelodysplastic Syndromes/therapy , Prognosis , Prospective Studies , Survival Rate , Young AdultABSTRACT
Although genomic alterations drive the pathogenesis of acute myeloid leukemia (AML), traditional classifications are largely based on morphology, and prototypic genetic founder lesions define only a small proportion of AML patients. The historical subdivision of primary/de novo AML and secondary AML has shown to variably correlate with genetic patterns. The combinatorial complexity and heterogeneity of AML genomic architecture may have thus far precluded genomic-based subclassification to identify distinct molecularly defined subtypes more reflective of shared pathogenesis. We integrated cytogenetic and gene sequencing data from a multicenter cohort of 6788 AML patients that were analyzed using standard and machine learning methods to generate a novel AML molecular subclassification with biologic correlates corresponding to underlying pathogenesis. Standard supervised analyses resulted in modest cross-validation accuracy when attempting to use molecular patterns to predict traditional pathomorphologic AML classifications. We performed unsupervised analysis by applying the Bayesian latent class method that identified 4 unique genomic clusters of distinct prognoses. Invariant genomic features driving each cluster were extracted and resulted in 97% cross-validation accuracy when used for genomic subclassification. Subclasses of AML defined by molecular signatures overlapped current pathomorphologic and clinically defined AML subtypes. We internally and externally validated our results and share an open-access molecular classification scheme for AML patients. Although the heterogeneity inherent in the genomic changes across nearly 7000 AML patients was too vast for traditional prediction methods, machine learning methods allowed for the definition of novel genomic AML subclasses, indicating that traditional pathomorphologic definitions may be less reflective of overlapping pathogenesis.
Subject(s)
Leukemia, Myeloid, Acute/genetics , Machine Learning , Bayes Theorem , Cytogenetics , Gene Expression Regulation, Leukemic , Genomics , Humans , Leukemia, Myeloid, Acute/classification , Leukemia, Myeloid, Acute/diagnosis , Mutation , Neoplasms, Second Primary/classification , Neoplasms, Second Primary/diagnosis , Neoplasms, Second Primary/genetics , Translocation, GeneticABSTRACT
The therapy algorithm for severe aplastic anaemia (sAA) is established but moderate AA (mAA), which likely reflects a more diverse pathogenic mechanism, often represents a treatment/management conundrum. A cohort of AA patients (n = 325) was queried for those with non-severe disease using stringent criteria including bone marrow hypocellularity and chronic persistence of moderately depressed blood counts. As a result, we have identified and analyzed pathological and clinical features in 85 mAA patients. Progression to sAA and direct clonal evolution (paroxysmal nocturnal haemoglobinuria/acute myeloid leukaemia; PNH/AML) occurred in 16%, 11% and 1% of mAA cases respectively. Of the mAA patients who received immunosuppressive therapy, 67% responded irrespective of time of initiation of therapy while conservatively managed patients showed no spontaneous remissions. Genomic analysis of mAA identified evidence of clonal haematopoiesis with both persisting and remitting patterns at low allelic frequencies; with more pronounced mutational burden in sAA. Most of the mAA patients have autoimmune pathogenesis similar to those with sAA, but mAA contains a mix of patients with diverse aetiologies. Although progression rates differed between mAA and sAA (P = 0·003), cumulative incidences of mortalities were only marginally different (P = 0·095). Our results provide guidance for diagnosis/management of mAA, a condition for which no current standard of care is established.
Subject(s)
Anemia, Aplastic/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Algorithms , Anemia, Aplastic/blood , Anemia, Aplastic/genetics , Anemia, Aplastic/therapy , Autoimmune Diseases/genetics , Autoimmune Diseases/pathology , Benzoates/therapeutic use , Blood Transfusion , Bone Marrow/pathology , Child , Child, Preschool , Clonal Evolution , Combined Modality Therapy , Danazol/therapeutic use , Disease Management , Disease Progression , Female , Hematopoiesis , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/pathology , Hemoglobinuria, Paroxysmal/etiology , Hemoglobinuria, Paroxysmal/pathology , Humans , Hydrazines/therapeutic use , Immunosuppressive Agents/therapeutic use , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Mutation , Pyrazoles/therapeutic use , Severity of Illness Index , Young AdultABSTRACT
The nucleoside analogue decitabine can deplete the epigenetic regulator DNA methyltransferase 1 (DNMT1), an effect that occurs, and is saturated at, low concentrations/doses. A reason to pursue this molecular-targeted effect instead of the DNA damage/cytotoxicity produced with high concentrations/doses, is that non-cytotoxic DNMT1-depletion can cytoreduce even p53-null myeloid malignancies while sparing normal haematopoiesis. We thus identified minimum doses of decitabine (0·1-0·2 mg/kg) that deplete DNMT1 without off-target anti-metabolite effects/cytotoxicity, and then administered these well-tolerated doses frequently 1-2X/week to increase S-phase dependent DNMT1-depletion, and used a Myeloid Malignancy Registry to evaluate long-term outcomes in 69 patients treated this way. Consistent with the scientific rationale, treatment was well-tolerated and durable responses were produced (~40%) in genetically heterogeneous disease and the very elderly.
Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Decitabine/therapeutic use , Myeloproliferative Disorders/drug therapy , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/pharmacology , Decitabine/pharmacology , Female , Humans , MaleABSTRACT
Myelodysplastic syndromes (MDS) arise in older adults through stepwise acquisitions of multiple somatic mutations. Here, analyzing 1809 MDS patients, we infer clonal architecture by using a stringent, the single-cell sequencing validated PyClone bioanalytic pipeline, and assess the position of the mutations within the clonal architecture. All 3,971 mutations are grouped based on their rank in the deduced clonal hierarchy (dominant and secondary). We evaluated how they affect the resultant morphology, progression, survival and response to therapies. Mutations of SF3B1, U2AF1, and TP53 are more likely to be dominant, those of ASXL1, CBL, and KRAS are secondary. Among distinct combinations of dominant/secondary mutations we identified 37 significant relationships, of which 12 affect clinical phenotypes, 5 cooperatively associate with poor prognosis. They also predict response to hypomethylating therapies. The clonal hierarchy has distinct ranking and the resultant invariant combinations of dominant/secondary mutations yield novel insights into the specific clinical phenotype of MDS.
Subject(s)
Mutation , Myelodysplastic Syndromes/etiology , Aged , Female , Hematopoiesis/genetics , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Male , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/pathology , Phenotype , Phosphoproteins/genetics , Primary Myelofibrosis/genetics , RNA Splicing Factors/genetics , Splicing Factor U2AF/genetics , Treatment Outcome , Tumor Suppressor Protein p53/genetics , Exome SequencingABSTRACT
Somatic mutations of the CUT-like homeobox 1 (CUX1) gene (CUX1 MT) can be found in myeloid neoplasms (MNs), in particular, in myelodysplastic syndromes (MDSs). The CUX1 locus is also deleted in 3 of 4 MN cases with -7/del(7q). A cohort of 1480 MN patients was used to characterize clinical features and clonal hierarchy associated with CUX1 MT and CUX1 deletions (CUX1 DEL) and to analyze their functional consequences in vitro. CUX1 MT were present in 4% of chronic MNs. CUX1 DEL were preferentially found in advanced cases (6%). Most MDS and acute myeloid leukemia (AML) patients with -7/del(7q) and up to 15% of MDS patients and 5% of AML patients diploid for the CUX1 locus exhibited downmodulated CUX1 expression. In 75% of mutant cases, CUX1 MT were heterozygous, whereas microdeletions and homozygous and compound-heterozygous mutations were less common. CUX MT/DEL were associated with worse survival compared with CUX1 WT Within the clonal hierarchy, 1 of 3 CUX1 MT served as founder events often followed by secondary BCOR and ASXL1 subclonal hits, whereas TET2 was the most common ancestral lesion, followed by subclonal CUX1 MT Comet assay of patients' bone marrow progenitor cells and leukemic cell lines performed in various experimental conditions revealed that frameshift mutations, hemizygous deletions, or experimental CUX1 knockdown decrease the repair of oxidized bases. These functional findings may explain why samples with either CUX1 MT or low CUX1 expression coincided with significantly higher numbers of somatic hits by whole-exome sequencing. Our findings implicate the DNA repair dysfunction resulting from CUX1 lesions in the pathogenesis of MNs, in which they lead to a mutator phenotype.
Subject(s)
Disease Susceptibility , Homeodomain Proteins/genetics , Myeloproliferative Disorders/diagnosis , Myeloproliferative Disorders/etiology , Repressor Proteins/genetics , Transcription Factors/genetics , Biomarkers , Chromosome Aberrations , Clonal Evolution/genetics , Female , Gene Expression Profiling , Genetic Association Studies , Genetic Predisposition to Disease , Homeodomain Proteins/metabolism , Humans , Kaplan-Meier Estimate , Leukocytes, Mononuclear , Loss of Heterozygosity , Male , Mutation , Myeloproliferative Disorders/mortality , Myeloproliferative Disorders/pathology , Phenotype , Polymorphism, Single Nucleotide , Prognosis , Repressor Proteins/metabolism , Sequence Deletion , Transcription Factors/metabolismABSTRACT
Therapy-related myeloid neoplasms (T-MN) are poorly characterized secondary hematological malignancies following chemotherapy/radiotherapy exposure. We compared the clinical and mutational characteristics of T-MN (n = 129) and primary myelodysplastic syndrome (P-MDS, n = 108) patients. Although the somatic mutation frequency was similar between T-MN and P-MDS patients (93% in both groups), the pattern was distinct. TP53 mutations were more frequent in T-MN (29.5 vs. 7%), while spliceosomal complex mutations were more common in P-MDS (56.5 vs. 25.6%). In contrast to P-MDS, the ring sideroblasts (RS) phenotype was not associated with better survival in T-MN, most probably due to genetic association with TP53 mutations. SF3B1 was mutated in 96% of P-MDS with ≥15% RS, but in only 32% T-MN. TP53 mutations were detected in 92% T-MN with ≥15% RS and SF3B1 wild-type cases. Interestingly, T-MN and P-MDS patients with "Very low" or "Low" Revised International Prognostic Scoring System (IPSS-R) showed similar biological and clinical characteristics. In a Cox regression analysis, TP53 mutation was a poor prognostic factor in T-MN, independent of IPSS-R cytogenetics, disease-modifying therapy, and NRAS mutation. Our data have direct implications for T-MN management and provide evidence that, in addition to conventional disease parameters, mutational analysis should be incorporated in T-MN risk stratification.
Subject(s)
Leukemia, Myeloid/etiology , Mutation , Myelodysplastic Syndromes/genetics , Neoplasms, Second Primary/etiology , Adult , Aged , Aged, 80 and over , Alleles , Biomarkers , Biopsy , Chromosome Aberrations , Cytogenetic Analysis , Diagnosis, Differential , Female , Humans , Leukemia, Myeloid/diagnosis , Leukemia, Myeloid/mortality , Male , Middle Aged , Mutation Rate , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/mortality , Neoplasms, Second Primary/diagnosis , Neoplasms, Second Primary/mortality , Prognosis , Young AdultABSTRACT
Nucleophosmin (NPM1) mutations are common in acute myeloid leukemia and are associated with high remission rates and prolonged survival with intensive chemotherapy. NPM1 mutations are rare in myelodysplastic syndromes (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and the clinical outcomes of these patients, when treated with intensive chemotherapy, are unknown. We retrospectively evaluated the clinicopathologic characteristics and the impact of therapy in 31 patients with MDS or MDS/MPN and NPM1 mutations. Next-generation sequencing was performed at diagnosis in 22 patients. Median age was 62 years (range, 19-86). Twenty-four patients (77%) had normal karyotype, and all had multilineage dysplasia. Most patients could be classified as MDS with excess blasts (19/31, 61%). NPM1 mutations were detected at a median allele frequency of 0.38 (range, 0.09-0.49). Mutation burden did not correlate with bone marrow blast frequency, and its clearance seemed to be associated with decreased morphologic dysplasia. Ten of the 31 patients (32%) received cytotoxic chemotherapy, 20 (65%) hypomethylating agents, and 1 (4%) lenalidomide. Sequential sequencing was available in 16 (52%) patients, and mutation burden correlated with disease status and response to therapy. Patients treated with chemotherapy had higher complete response rates (90% vs 28%, P = .004), longer median progression-free survival (not reached vs 7.5 months, P = .023), and overall survival (not reached vs 16 months, P = .047). Intensive chemotherapy and allogeneic stem cell transplantation (SCT) may be associated with improved clinical outcomes in patients with NPM1-mutated MDS or MDS/MPN who are candidates for this form of therapy.
Subject(s)
Mutation , Myelodysplastic-Myeloproliferative Diseases/diagnosis , Myelodysplastic-Myeloproliferative Diseases/drug therapy , Nuclear Proteins/genetics , Adult , Aged , Aged, 80 and over , High-Throughput Nucleotide Sequencing , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/drug therapy , Middle Aged , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/drug therapy , Myelodysplastic-Myeloproliferative Diseases/genetics , Myelodysplastic-Myeloproliferative Diseases/mortality , Nucleophosmin , Remission Induction , Retrospective Studies , Survival Analysis , Treatment Outcome , Young AdultABSTRACT
Somatic TET2 mutations (TET2 MT) are frequent in myeloid neoplasia (MN), particularly chronic myelomonocytic leukemia (CMML). TET2 MT includes mostly loss-of-function/hypomorphic hits. Impaired TET2 activity skews differentiation of hematopoietic stem cells toward proliferating myeloid precursors. This study was prompted by the observation of frequent biallelic TET2 gene inactivations (biTET2 i ) in CMML. We speculated that biTET2 i might be associated with distinct clinicohematological features. We analyzed TET2 MT in 1045 patients with MN. Of 82 biTET2 i cases, 66 were biTET2 MT, 13 were hemizygous TET2 MT, and 3 were homozygous TET2 MT (uniparental disomy); the remaining patients (denoted biTET2 - hereafter) were either monoallelic TET2 MT (n = 96) or wild-type TET2 (n = 823). Truncation mutations were found in 83% of biTET2 i vs 65% of biTET2 - cases (P = .02). TET2 hits were founder lesions in 72% of biTET2 i vs 38% of biTET2 - cases (P < .0001). In biTET2 i , significantly concurrent hits included SRSF2 MT (33%; P < .0001) and KRAS/NRAS MT (16%; P = .03) as compared with biTET2 - When the first TET2 hit was ancestral in biTET2 i , the most common subsequent hits affected a second TET2 MT, followed by SRSF2 MT, ASXL1 MT, RAS MT, and DNMT3A MT BiTET2 i patients without any monocytosis showed an absence of SRSF2 MT BiTET2 i patients were older and had monocytosis, CMML, normal karyotypes, and lower-risk disease compared with biTET2 - patients. Hence, while a second TET2 hit occurred frequently, biTET2 i did not portend faster progression but rather determined monocytic differentiation, consistent with its prevalence in CMML. Additionally, biTET2 i showed lower odds of cytopenias and marrow blasts (≥5%) and higher odds of myeloid dysplasia and marrow hypercellularity. Thus, biTET2 i might represent an auxiliary assessment tool in MN.
Subject(s)
DNA-Binding Proteins/genetics , Myelodysplastic Syndromes/genetics , Proto-Oncogene Proteins/genetics , Adolescent , Adult , Aged , Aged, 80 and over , DNA-Binding Proteins/metabolism , Dioxygenases , Female , Gene Silencing , Humans , Male , Middle Aged , Mutation , Myelodysplastic Syndromes/blood , Myelodysplastic Syndromes/pathology , Phenotype , Prognosis , Proto-Oncogene Proteins/metabolism , Young AdultABSTRACT
The interferon (IFN) system represents the first line of defense against a wide range of viruses. Virus infection rapidly triggers the transcriptional induction of IFN-ß and IFN Stimulated Genes (ISGs), whose protein products act as viral restriction factors by interfering with specific stages of virus life cycle, such as entry, transcription, translation, genome replication, assembly and egress. Here, we report a new mode of action of an ISG, IFN-induced TDRD7 (tudor domain containing 7) inhibited paramyxovirus replication by inhibiting autophagy. TDRD7 was identified as an antiviral gene by a high throughput screen of an ISG shRNA library for blocking IFN's protective effect against Sendai virus (SeV) replication. The antiviral activity of TDRD7 against SeV, human parainfluenza virus 3 and respiratory syncytial virus was confirmed by its genetic ablation or ectopic expression in several types of mouse and human cells. TDRD7's antiviral action was mediated by its ability to inhibit autophagy, a cellular catabolic process which was robustly induced by SeV infection and required for its replication. Mechanistic investigation revealed that TDRD7 interfered with the activation of AMP-dependent kinase (AMPK), an enzyme required for initiating autophagy. AMPK activity was required for efficient replication of several paramyxoviruses, as demonstrated by its genetic ablation or inhibition of its activity by TDRD7 or chemical inhibitors. Therefore, our study has identified a new antiviral ISG with a new mode of action.
Subject(s)
Antiviral Agents/pharmacology , Autophagy , Interferons/pharmacology , Paramyxovirinae/physiology , Ribonucleoproteins/physiology , Virus Replication/drug effects , Animals , Autophagy/genetics , Autophagy/immunology , Cells, Cultured , Gene Expression Regulation/drug effects , HEK293 Cells , HeLa Cells , Humans , Immunity, Innate/drug effects , Immunity, Innate/genetics , Mice , Mice, Inbred C57BL , Ribonucleoproteins/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , Virus Replication/geneticsABSTRACT
To elucidate differential roles of mutations in myelodysplastic syndromes (MDS), we investigated clonal dynamics using whole-exome and/or targeted sequencing of 699 patients, of whom 122 were analyzed longitudinally. Including the results from previous reports, we assessed a total of 2,250 patients for mutational enrichment patterns. During progression, the number of mutations, their diversity and clone sizes increased, with alterations frequently present in dominant clones with or without their sweeping previous clones. Enriched in secondary acute myeloid leukemia (sAML; in comparison to high-risk MDS), FLT3, PTPN11, WT1, IDH1, NPM1, IDH2 and NRAS mutations (type 1) tended to be newly acquired, and were associated with faster sAML progression and a shorter overall survival time. Significantly enriched in high-risk MDS (in comparison to low-risk MDS), TP53, GATA2, KRAS, RUNX1, STAG2, ASXL1, ZRSR2 and TET2 mutations (type 2) had a weaker impact on sAML progression and overall survival than type-1 mutations. The distinct roles of type-1 and type-2 mutations suggest their potential utility in disease monitoring.