RESUMEN
The recent application of whole exome or whole genome sequencing unveiled a plethora of germline variants predisposing to myeloid disorders, particularly myelodysplastic neoplasms. The presence of such variants in patients with myelodysplastic syndromes has important clinical repercussions for haematopoietic stem-cell transplantation, from donor selection and conditioning regimen to graft-versus-host disease prophylaxis and genetic counselling for relatives. No international guidelines exist to harmonise management approaches to this particular clinical scenario. Moreover, the application of germline testing, and how this informs clinical decisions, differs according to the expertise of individual clinical practices and according to different countries, health-care systems, and legislations. Leveraging the global span of the European Society for Blood and Marrow Transplantation (EBMT) network, we took a snapshot of the current European situation on these matters by disseminating an electronic survey to EBMT centres experienced in myelodysplastic syndromes transplantation. An international group of haematologists, transplantation physicians, paediatricians, nurses, and experts in molecular biology and constitutional genetics with experience in myelodysplastic syndromes contributed to this Position Paper. The panel met during multiple online meetings to discuss the results of the EBMT survey and to establish suggested harmonised guidelines for such clinical situations, which are presented here.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Síndromes Mielodisplásicos , Neoplasias , Humanos , Trasplante Homólogo , Trasplante de Células Madre Hematopoyéticas/métodos , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Encuestas y Cuestionarios , Acondicionamiento Pretrasplante/métodos , Susceptibilidad a Enfermedades , Enfermedad Injerto contra Huésped/prevención & controlRESUMEN
Azacitidine is a mainstay of therapy for myelodysplastic syndrome (MDS)-related diseases. The purpose of our study is to elucidate the effect of gene mutations on hematological response and overall survival (OS), particularly focusing on their posttreatment clone size. We enrolled a total of 449 patients with MDS or related myeloid neoplasms. They were analyzed for gene mutations in pretreatment (n = 449) and posttreatment (n = 289) bone marrow samples using targeted-capture sequencing to assess the impact of gene mutations and their posttreatment clone size on treatment outcomes. In Cox proportional hazard modeling, multihit TP53 mutation (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.42-2.91; P < .001), EZH2 mutation (HR, 1.71; 95% CI, 1.14-2.54; P = .009), and DDX41 mutation (HR, 0.33; 95% CI, 0.17-0.62; P < .001), together with age, high-risk karyotypes, low platelets, and high blast counts, independently predicted OS. Posttreatment clone size accounting for all drivers significantly correlated with International Working Group (IWG) response (P < .001, using trend test), except for that of DDX41-mutated clones, which did not predict IWG response. Combined, IWG response and posttreatment clone size further improved the prediction of the original model and even that of a recently proposed molecular prediction model, the molecular International Prognostic Scoring System (IPSS-M; c-index, 0.653 vs 0.688; P < .001, using likelihood ratio test). In conclusion, evaluation of posttreatment clone size, together with the pretreatment mutational profile as well as the IWG response play a role in better prognostication of azacitidine-treated patients with myelodysplasia.
Asunto(s)
Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Neoplasias , Humanos , Pronóstico , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Resultado del Tratamiento , AzacitidinaRESUMEN
Deleterious germ line DDX41 variants confer risk for myeloid neoplasms (MNs) and less frequently for lymphoid malignancies, with autosomal dominant inheritance and an estimated prevalence of 3% among MNs. Germ line DDX41 variants include truncating alleles that comprise about two-thirds of all alleles, missense variants located preferentially within the DEAD-box domain, and deletion variants. The identification of a truncating allele on tumor-based molecular profiling should prompt germ line genetic testing because >95% of such alleles are germ line. Somatic mutation of the wild-type DDX41 allele occurs in about half of MNs with germ line DDX41 alleles, typically in exons encoding the helicase domain and most frequently as R525H. Several aspects of deleterious germ line DDX41 alleles are noteworthy: (1) certain variants are common in particular populations, (2) MNs develop at older ages typical of de novo disease, challenging the paradigm that inherited cancer risk always causes disease in young people, (3) despite equal frequencies of these variants in men and women, men progress to MNs more frequently, suggesting a gender-specific effect on myeloid leukemogenesis, and (4) individuals with deleterious germ line DDX41 variants develop acute severe graft-versus-host disease after allogeneic hematopoietic cell transplantation with wild-type donors more than others unless they receive posttransplant cyclophosphamide, suggesting a proinflammatory milieu that stimulates donor-derived T cells. Biochemical studies and animal models have identified DDX41's ability to interact with double-stranded DNA and RNA:DNA hybrids with roles in messenger RNA splicing, ribosomal RNAs or small nucleolar RNAs processing, and modulation of innate immunity, disruption of which could promote inflammation and drive tumorigenesis.
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ARN Helicasas DEAD-box , Leucemia Mieloide , Trastornos Mieloproliferativos , Animales , Femenino , ARN Helicasas DEAD-box/genética , Mutación de Línea Germinal , Trastornos Mieloproliferativos/genética , ARN Mensajero , Humanos , MasculinoRESUMEN
Germ line DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications, many important features of DDX41-mutated MNs remain to be elucidated. Here we performed a comprehensive characterization of DDX41-mutated MNs, enrolling a total of 346 patients with DDX41 pathogenic/likely-pathogenic (P/LP) germ line variants and/or somatic mutations from 9082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients. P/LP DDX41 germ line variants explained â¼80% of known germ line predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n = 4461) compared with the general population of Japan (n = 20 238). This enrichment of DDX41 risk alleles was much more prominent in male than female (20.7 vs 5.0). P/LP DDX41 variants conferred a large risk of developing MNs, which was negligible until 40 years of age but rapidly increased to 49% by 90 years of age. Patients with myelodysplastic syndromes (MDS) along with a DDX41-mutation rapidly progressed to acute myeloid leukemia (AML), which was however, confined to those having truncating variants. Comutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and WT cases, in which none of the comutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multihit allelic status, on survival was almost completely mitigated by the presence of DDX41 mutations. Finally, outcomes were not affected by the conventional risk stratifications including the revised/molecular International Prognostic Scoring System. Our findings establish that MDS with DDX41-mutation defines a unique subtype of MNs that is distinct from other MNs.
Asunto(s)
ARN Helicasas DEAD-box , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Adulto , Anciano de 80 o más Años , Femenino , Humanos , Masculino , ARN Helicasas DEAD-box/genética , Células Germinativas , Leucemia Mieloide Aguda/genética , Mutación , Síndromes Mielodisplásicos/genética , Trastornos Mieloproliferativos/genéticaRESUMEN
Similar with myelodysplastic syndromes (MDS), aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are the major bone marrow failure syndromes. Approximately 10-20% of patients with AA/PNH present with transformation into MDS. Clonal hematopoiesis in AA/PNH affected by karyotypic abnormalities and genetic mutations should be discriminated from MDS clone, which is sometimes difficult due to shared genetic events among these diseases. In patients with AA/PNH, clones with UPD6p and PIGA mutations are selected under autoimmune pressure, and those with DNMT3A, ASXL1, and TET2 mutations originated from clonal hematopoiesis of indeterminate potential (CHIP) frequently identified in elderly healthy individuals. In patients with cytopenia, a single CHIP mutation is insufficient for MDS presentation. However, TP53 and U2AF1 mutations, which are not in the list of typical CHIP mutations, are observed in patients with AA with future MDS transformation. Therefore, clonal hematopoiesis in AA/PNH, partially overlapping the MDS clone, is caused by autoimmunity and originates from CHIP, demonstrating distinct genetic profiles.
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Anemia Aplásica , Hemoglobinuria Paroxística , Síndromes Mielodisplásicos , Anciano , Anemia Aplásica/genética , Hematopoyesis Clonal , Hematopoyesis/genética , Hemoglobinuria Paroxística/genética , Humanos , Síndromes Mielodisplásicos/genética , Factor de Empalme U2AF/genéticaRESUMEN
Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome, whole-exome, and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains and amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains and amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL. SIGNIFICANCE: This study reveals the major role of gains, amplifications, and mutations of EPOR and JAK2 in the pathogenesis of pure erythroleukemia. Their frequent response to ruxolitinib in patient-derived xenograft and cell culture models highlights a possible therapeutic role of JAK2 inhibition for erythroleukemia with EPOR/JAK2-involving lesions. This article is highlighted in the In This Issue feature, p. 369.
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Janus Quinasa 2 , Leucemia Eritroblástica Aguda , Leucemia Mieloide Aguda , Receptores de Eritropoyetina , Exoma , Humanos , Janus Quinasa 2/genética , Leucemia Eritroblástica Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Mutación , Pronóstico , Receptores de Eritropoyetina/genéticaRESUMEN
Myxofibrosarcoma (MFS) is a rare subtype of sarcoma, whose genetic basis is poorly understood. We analyzed 69 MFS cases using whole-genome (WGS), whole-exome (WES) and/or targeted-sequencing (TS). Newly sequenced genomic data were combined with additional deposited 116 MFS samples. WGS identified a high number of structural variations (SVs) per tumor most frequently affecting the TP53 and RB1 loci, 40% of tumors showed a BRCAness-associated mutation signature, and evidence of chromothripsis was found in all cases. Most frequently mutated/copy number altered genes affected known disease drivers such as TP53 (56.2%), CDKN2A/B (29.7%), RB1 (27.0%), ATRX (19.5%) and HDLBP (18.9%). Several previously unappreciated genetic aberrations including MUC17, FLG and ZNF780A were identified in more than 20% of patients. Longitudinal analysis of paired diagnosis and relapse time points revealed a 1.2-fold mutation number increase accompanied with substantial changes in clonal composition over time. Our study highlights the genetic complexity underlying sarcomagenesis of MFS.
Asunto(s)
Fibrosarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Adulto , Variaciones en el Número de Copia de ADN , Exoma , Fibrosarcoma/genética , Humanos , Mutación , Recurrencia Local de Neoplasia/genética , Sarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Secuenciación del ExomaRESUMEN
Clonal hematopoiesis (CH) in apparently healthy individuals is implicated in the development of hematological malignancies (HM) and cardiovascular diseases. Previous studies of CH analyzed either single-nucleotide variants and indels (SNVs/indels) or copy number alterations (CNAs), but not both. Here, using a combination of targeted sequencing of 23 CH-related genes and array-based CNA detection of blood-derived DNA, we have delineated the landscape of CH-related SNVs/indels and CNAs in 11,234 individuals without HM from the BioBank Japan cohort, including 672 individuals with subsequent HM development, and studied the effects of these somatic alterations on mortality from HM and cardiovascular disease, as well as on hematological and cardiovascular phenotypes. The total number of both types of CH-related lesions and their clone size positively correlated with blood count abnormalities and mortality from HM. CH-related SNVs/indels and CNAs exhibited statistically significant co-occurrence in the same individuals. In particular, co-occurrence of SNVs/indels and CNAs affecting DNMT3A, TET2, JAK2 and TP53 resulted in biallelic alterations of these genes and was associated with higher HM mortality. Co-occurrence of SNVs/indels and CNAs also modulated risks for cardiovascular mortality. These findings highlight the importance of detecting both SNVs/indels and CNAs in the evaluation of CH.
Asunto(s)
Enfermedades Cardiovasculares/genética , Hematopoyesis Clonal/genética , Variaciones en el Número de Copia de ADN/genética , Neoplasias Hematológicas/genética , Polimorfismo de Nucleótido Simple/genética , Anciano , Biomarcadores de Tumor/genética , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/patología , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Proteínas de Unión al ADN/genética , Dioxigenasas , Femenino , Marcadores Genéticos/genética , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/patología , Células Madre Hematopoyéticas/citología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación INDEL/genética , Janus Quinasa 2/genética , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Upper urinary tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Its molecular pathogenesis, however, is poorly understood, with no useful biomarkers available for accurate diagnosis and molecular classification. Through an integrated genetic study involving 199 UTUC samples, we delineate the landscape of genetic alterations in UTUC enabling genetic/molecular classification. According to the mutational status of TP53, MDM2, RAS, and FGFR3, UTUC is classified into five subtypes having discrete profiles of gene expression, tumor location/histology, and clinical outcome, which is largely recapitulated in an independent UTUC cohort. Sequencing of urine sediment-derived DNA has a high diagnostic value for UTUC with 82.2% sensitivity and 100% specificity. These results provide a solid basis for better diagnosis and management of UTUC.
Asunto(s)
Biomarcadores de Tumor/orina , Carcinoma de Células Transicionales/diagnóstico , Carcinoma de Células Transicionales/genética , Neoplasias Ureterales/diagnóstico , Neoplasias Ureterales/genética , Anciano , Biomarcadores de Tumor/genética , Carcinoma de Células Transicionales/mortalidad , Metilación de ADN , Femenino , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Mutación , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas c-mdm2/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Proteína p53 Supresora de Tumor/genética , Neoplasias Ureterales/mortalidad , Proteínas ras/genéticaRESUMEN
Recent advances in sequencing technologies have increased the detection rate for identifying germline mutations that predispose an individual to various myeloid neoplasms and somatic mutations acquired during progression from myelodysplastic syndromes (MDS) to acute myeloid leukemia (AML). In addition to pediatric subjects, adult patients were analyzed in order to obtain a complete spectrum of driver mutations in germline cells and/or somatic tumor samples. As shown in several recent studies, such driver mutations are acquired in a gene-specific fashion. DDX41 mutations are observed in germline cells long before MDS presentation. SAMD9/SAMD9L germline mutations associated with defective hematopoiesis account for recurrent and familial -7/del (7q) lesions, which result in the removal of the disadvantageous allele. Additionally, MDS cases in younger population display compound heterozygous germline mutations in the Shwachman-Diamond syndrome-associated SBDS gene. In peripheral blood samples from healthy elderly individuals, DNMT3A, TET2, and ASXL1 somatic mutations are usually detected due to age-related clonal hematopoiesis and are considered to be a risk factor for hematological neoplasms. In MDS, mutations of genes, such as NRAS and FLT3, designated as type-1 genes, are significantly associated with leukemic evolution. On the other hand, mutations in type-2 genes, including RUNX1 and GATA2, are related to progression from low risk MDS to high risk MDS.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Adulto , Anciano , Niño , Mutación de Línea Germinal , Humanos , Péptidos y Proteínas de Señalización Intracelular , Leucemia Mieloide Aguda/genética , Mutación , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genéticaRESUMEN
Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.
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Crisis Blástica/genética , Evolución Clonal/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Crisis Blástica/tratamiento farmacológico , Crisis Blástica/patología , Proteínas Sanguíneas/genética , Estudios de Cohortes , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/patología , Masculino , Persona de Mediana Edad , Mutación , Proteínas de Fusión Oncogénica/genética , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteína Proto-Oncogénica c-ets-2/genética , Secuenciación del Exoma , Adulto JovenRESUMEN
Extranodal NK/T cell lymphomas (ENKTCLs) are aggressive Epstein-Barr virus-associated T/NK neoplasms that predominantly affect Asians. To explore the causative somatic events, we conducted a comprehensive genetic analysis of 19 ENKTCL patients by whole-genome (N = 2), whole-exome (N = 16), and targeted sequencing (N = 15). Commonly deregulated gene pathways in ENKTCLs included epigenetic modifiers (58%, 11/19) followed by human leukocyte antigens (HLAs) and related genes including HLA-A, B2M, TAP1, CD274, and PDCD1LG2 (32%, 6/19), and JAK-STAT pathway (26%, 5/19). Conspicuously, loss-of-function mutations in HLA-A were recurrently identified in ENKTCLs (16%, 3/19). HLA protein expression was examined by immunohistochemistry in 16 patients and lower expression was associated with advanced stages at presentation (p = .007). In conclusion, the defective antigen presenting pathway is common and related to disease progression, suggesting immune escape as a pathogenic mechanism of ENKTCLs.
Asunto(s)
Infecciones por Virus de Epstein-Barr , Linfoma Extranodal de Células NK-T , Herpesvirus Humano 4 , Humanos , Inmunohistoquímica , Linfoma Extranodal de Células NK-T/genética , MutaciónRESUMEN
Somatic mutations constitute key elements of the pathogenesis of myelodysplastic syndromes (MDS), a group of clonal hematologic neoplasms characterized by cytopenias, dysplasia and leukemic evolution. Whole exome sequencing followed by targeted deep sequencing in patients with MDS and related diseases has been performed cross-sectionally and serially. Bioinformatic analysis and confirmatory sequencing led to detection of in 1458 genes affected by somatic alterations, and identification of known and new driver events. For each patient, mutation spectrum as well as clonal hierarchy was determined and for each significantly mutated gene, its role in the clonal succession established. This approach allowed for a dynamic definition of MDS mutatome, including the spectrum of founding mutations and subsequent secondary mutational patterns. We demonstrate that certain founder events determine the mode and speed of disease progression, while secondary mutations may further modulate phenotypic features. Combinations of founder and secondary mutations further contribute to the phenotypic diversity but categorical grouping of cases based on the type of founder mutations may better define molecular subtypes of MDS and correlates with clinical parameters.
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Efecto Fundador , Neoplasias Hematológicas/genética , Mutación , Síndromes Mielodisplásicos/genética , Polimorfismo de Nucleótido Simple , Estudio de Asociación del Genoma Completo , HumanosRESUMEN
Recent genetic studies using high-throughput sequencing have disclosed genetic alterations in B-cell precursor acute lymphoblastic leukemia (B-ALL). However, their effects on clinical outcomes have not been fully investigated. To address this, we comprehensively examined genetic alterations and their prognostic impact in a large series of pediatric B-ALL cases. We performed targeted capture sequencing in a total of 1003 pediatric patients with B-ALL from 2 Japanese cohorts. Transcriptome sequencing (n = 116) and/or array-based gene expression analysis (n = 120) were also performed in 203 (84%) of 243 patients who were not categorized into any disease subgroup by panel sequencing or routine reverse transcription polymerase chain reaction analysis for major fusions in B-ALL. Our panel sequencing identified novel recurrent mutations in 2 genes (CCND3 and CIC), and both had positive correlations with ETV6-RUNX1 and hypodiploid ALL, respectively. In addition, positive correlations were also newly reported between TCF3-PBX1 ALL with PHF6 mutations. In multivariate Cox proportional hazards regression models for overall survival, TP53 mutation/deletion, hypodiploid, and MEF2D fusions were selected in both cohorts. For TP53 mutations, the negative effect on overall survival was confirmed in an independent external cohort (n = 466). TP53 mutation was frequently found in IGH-DUX4 (5 of 57 [9%]) ALL, with 4 cases having 17p LOH and negatively affecting overall survival therein, whereas TP53 mutation was not associated with poor outcomes among NCI (National Cancer Institute) standard risk (SR) patients. A conventional treatment approach might be enough, and further treatment intensification might not be necessary, for patients with TP53 mutations if they are categorized into NCI SR.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Linfocitos B , Niño , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , PronósticoRESUMEN
Morphologic interpretation is the standard in diagnosing myelodysplastic syndrome (MDS), but it has limitations, such as varying reliability in pathologic evaluation and lack of integration with genetic data. Somatic events shape morphologic features, but the complexity of morphologic and genetic changes makes clear associations challenging. This article interrogates novel clinical subtypes of MDS using a machine-learning technique devised to identify patterns of cooccurrence among morphologic features and genomic events. We sequenced 1079 MDS patients and analyzed bone marrow morphologic alterations and other clinical features. A total of 1929 somatic mutations were identified. Five distinct morphologic profiles with unique clinical characteristics were defined. Seventy-seven percent of higher-risk patients clustered in profile 1. All lower-risk (LR) patients clustered into the remaining 4 profiles: profile 2 was characterized by pancytopenia, profile 3 by monocytosis, profile 4 by elevated megakaryocytes, and profile 5 by erythroid dysplasia. These profiles could also separate patients with different prognoses. LR MDS patients were classified into 8 genetic signatures (eg, signature A had TET2 mutations, signature B had both TET2 and SRSF2 mutations, and signature G had SF3B1 mutations), demonstrating association with specific morphologic profiles. Six morphologic profiles/genetic signature associations were confirmed in a separate analysis of an independent cohort. Our study demonstrates that nonrandom or even pathognomonic relationships between morphology and genotype to define clinical features can be identified. This is the first comprehensive implementation of machine-learning algorithms to elucidate potential intrinsic interdependencies among genetic lesions, morphologies, and clinical prognostic in attributes of MDS.
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Aprendizaje Automático , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Adulto , Anciano , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
Loss-of-function TET2 mutations (TET2MT) are common in myeloid neoplasia. TET2, a DNA dioxygenase, requires 2-oxoglutarate and Fe(II) to oxidize 5-methylcytosine. TET2MT thus result in hypermethylation and transcriptional repression. Ascorbic acid (AA) increases dioxygenase activity by facilitating Fe(III)/Fe(II) redox reaction and may alleviate some biological consequences of TET2MT by restoring dioxygenase activity. Here, we report the utility of AA in the prevention of TET2MT myeloid neoplasia (MN), clarify the mechanistic underpinning of the TET2-AA interactions, and demonstrate that the ability of AA to restore TET2 activity in cells depends on N- and C-terminal lysine acetylation and nature of TET2MT. Consequently, pharmacologic modulation of acetyltransferases and histone deacetylases may regulate TET dioxygenase-dependent AA effects. Thus, our study highlights the contribution of factors that may enhance or attenuate AA effects on TET2 and provides a rationale for novel therapeutic approaches including combinations of AA with class I/II HDAC inhibitor or sirtuin activators in TET2MT leukemia.
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Ácido Ascórbico/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Mutación/genética , Acetilación , Administración Oral , Animales , Ácido Ascórbico/administración & dosificación , Ácido Ascórbico/farmacología , Proliferación Celular/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Dioxigenasas , Células HEK293 , Humanos , Células K562 , Lisina/genética , Ratones , Proteínas Proto-Oncogénicas/metabolismoRESUMEN
STAG2 encodes a cohesin component and is frequently mutated in myeloid neoplasms, showing highly significant comutation patterns with other drivers, including RUNX1. However, the molecular basis of cohesin-mutated leukemogenesis remains poorly understood. Here we show a critical role of an interplay between STAG2 and RUNX1 in the regulation of enhancer-promoter looping and transcription in hematopoiesis. Combined loss of STAG2 and RUNX1, which colocalize at enhancer-rich, CTCF-deficient sites, synergistically attenuates enhancer-promoter loops, particularly at sites enriched for RNA polymerase II and Mediator, and deregulates gene expression, leading to myeloid-skewed expansion of hematopoietic stem/progenitor cells (HSPC) and myelodysplastic syndromes (MDS) in mice. Attenuated enhancer-promoter loops in STAG2/RUNX1-deficient cells are associated with downregulation of genes with high basal transcriptional pausing, which are important for regulation of HSPCs. Downregulation of high-pausing genes is also confirmed in STAG2-cohesin-mutated primary leukemia samples. Our results highlight a unique STAG2-RUNX1 interplay in gene regulation and provide insights into cohesin-mutated leukemogenesis. SIGNIFICANCE: We demonstrate a critical role of an interplay between STAG2 and a master transcription factor of hematopoiesis, RUNX1, in MDS development, and further reveal their contribution to regulation of high-order chromatin structures, particularly enhancer-promoter looping, and the link between transcriptional pausing and selective gene dysregulation caused by cohesin deficiency.This article is highlighted in the In This Issue feature, p. 747.
Asunto(s)
Proteínas de Ciclo Celular/deficiencia , Cromatina/genética , Proteínas Cromosómicas no Histona/deficiencia , Subunidad alfa 2 del Factor de Unión al Sitio Principal/deficiencia , Síndromes Mielodisplásicos/etiología , Animales , Regulación de la Expresión Génica , Humanos , Ratones , Ratones Noqueados , CohesinasRESUMEN
Loss-of-function mutations in ten-eleven translocation-2 (TET2) are recurrent events in acute myeloid leukemia (AML) as well as in preleukemic hematopoietic stem cells (HSCs) of age-related clonal hematopoiesis. TET3 mutations are infrequent in AML, but the level of TET3 expression in HSCs has been found to decline with age. We examined the impact of gradual decrease of TET function in AML development by generating mice with Tet deficiency at various degrees. Tet2f/f and Tet3f/f mice were crossed with mice expressing Mx1-Cre to generate Tet2f/wtTet3f/fMx-Cre+ (T2ΔT3), Tet2f/fTet3f/wtMx-Cre+ (ΔT2T3), and Tet2f/fTet3f/fMx-Cre+ (ΔT2ΔT3) mice. All ΔT2ΔT3 mice died of aggressive AML at a median survival of 10.7 weeks. By comparison, T2ΔT3 and ΔT2T3 mice developed AML at longer latencies, with a median survival of â¼27 weeks. Remarkably, all 9 T2ΔT3 and 8 ΔT2T3 mice with AML showed inactivation of the remaining nontargeted Tet2 or Tet3 allele, respectively, owing to exonic loss in either gene or stop-gain mutations in Tet3. Recurrent mutations other than Tet3 were not noted in any mice by whole-exome sequencing. Spontaneous inactivation of residual Tet2 or Tet3 alleles is a recurrent genetic event during the development of AML with Tet insufficiency.
Asunto(s)
Leucemia Mieloide Aguda , Proteínas Proto-Oncogénicas , Animales , Proteínas de Unión al ADN/genética , Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/genética , Ratones , Mutación , Proteínas Proto-Oncogénicas/genéticaRESUMEN
Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer1-3. However, how such cycles affect the clonal composition of tissues, particularly in terms of cancer development, remains unknown. Here we show that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodelling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2, ZC3H12A, PIGR and HNRNPF genes and are implicated in the downregulation of IL-17 and other pro-inflammatory signals. Mutational profiles vary substantially between colitis-associated cancer and non-dysplastic tissues in ulcerative colitis, which indicates that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ are highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in both sporadic and colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, we found that tumour formation was significantly attenuated in Nfkbiz-mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which reveal unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.