RESUMEN
Individuals with age-related clonal hematopoiesis (CH) are at greater risk for hematologic malignancies and cardiovascular diseases. However, predictive preclinical animal models to recapitulate the spectrum of human CH are lacking. Through error-corrected sequencing of 56 human CH/myeloid malignancy genes, we identified natural CH driver mutations in aged rhesus macaques matching genes somatically mutated in human CH, with DNMT3A mutations being the most frequent. A CH model in young adult macaques was generated via autologous transplantation of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9-mediated gene-edited hematopoietic stem and progenitor cells (HSPCs), targeting the top human CH genes with loss-of-function (LOF) mutations. Long-term follow-up revealed reproducible and significant expansion of multiple HSPC clones with heterozygous TET2 LOF mutations, compared with minimal expansion of clones bearing other mutations. Although the blood counts of these CH macaques were normal, their bone marrows were hypercellular and myeloid-predominant. TET2-disrupted myeloid colony-forming units isolated from these animals showed a distinct hyperinflammatory gene expression profile compared with wild type. In addition, mature macrophages purified from the CH macaques showed elevated NLRP3 inflammasome activity and increased interleukin-1ß (IL-1ß) and IL-6 production. The model was used to test the impact of IL-6 blockage by tocilizumab, documenting a slowing of TET2-mutated expansion, suggesting that interruption of the IL-6 axis may remove the selective advantage of mutant HSPCs. These findings provide a model for examining the pathophysiology of CH and give insights into potential therapeutic interventions.
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Hematopoyesis Clonal , Dioxigenasas , Humanos , Adulto Joven , Animales , Anciano , Hematopoyesis Clonal/genética , Hematopoyesis/genética , Interleucina-1beta/genética , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Macaca mulatta , Proteína 9 Asociada a CRISPR , Interleucina-6/genética , Células Clonales , Proteínas de Unión al ADN/genética , Dioxigenasas/genéticaRESUMEN
BACKGROUND: Patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusions. Luspatercept, a recombinant fusion protein that binds transforming growth factor ß superfamily ligands to reduce SMAD2 and SMAD3 signaling, showed promising results in a phase 2 study. METHODS: In a double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients with very-low-risk, low-risk, or intermediate-risk myelodysplastic syndromes (defined according to the Revised International Prognostic Scoring System) with ring sideroblasts who had been receiving regular red-cell transfusions to receive either luspatercept (at a dose of 1.0 up to 1.75 mg per kilogram of body weight) or placebo, administered subcutaneously every 3 weeks. The primary end point was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary end point was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48. RESULTS: Of the 229 patients enrolled, 153 were randomly assigned to receive luspatercept and 76 to receive placebo; the baseline characteristics of the patients were balanced. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, as compared with 13% of those in the placebo group (P<0.001). A higher percentage of patients in the luspatercept group than in the placebo group met the key secondary end point (28% vs. 8% for weeks 1 through 24, and 33% vs. 12% for weeks 1 through 48; P<0.001 for both comparisons). The most common luspatercept-associated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time. CONCLUSIONS: Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesis-stimulating agents or who had discontinued such agents owing to an adverse event. (Funded by Celgene and Acceleron Pharma; MEDALIST ClinicalTrials.gov number, NCT02631070; EudraCT number, 2015-003454-41.).
Asunto(s)
Receptores de Activinas Tipo II/uso terapéutico , Anemia Sideroblástica/tratamiento farmacológico , Transfusión de Eritrocitos , Hematínicos/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Proteínas Recombinantes de Fusión/uso terapéutico , Receptores de Activinas Tipo II/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Anemia Sideroblástica/terapia , Método Doble Ciego , Femenino , Hematínicos/efectos adversos , Hemoglobinas/análisis , Humanos , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Infusiones Subcutáneas , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/terapia , Proteínas Recombinantes de Fusión/efectos adversosRESUMEN
We have reported previously that CD33hi myeloid-derived suppressor cells (MDSCs) play a direct role in the pathogenesis of myelodysplastic syndromes (MDSs) and that their sustained activation contributes to hematopoietic and immune impairment, including modulation of PD1/PDL1. MDSCs can also limit the clinical activity of immune checkpoint inhibition in solid malignancies. We hypothesized that depletion of MDSCs may ameliorate resistance to checkpoint inhibitors and, hence, targeted them with AMV564 combined with anti-PD1 in MDS bone marrow (BM) mononuclear cells (MNCs) enhanced activation of cytotoxic T cells. AMV564 was active in vivo in a leukemia xenograft model when co-administered with healthy donor peripheral blood MNCs (PBMCs). Our findings provide a strong rationale for clinical investigation of AMV564 as a single agent or in combination with an anti-PD1 antibody and in particular for treatment of cancers resistant to checkpoint inhibitors.
Asunto(s)
Anticuerpos Biespecíficos , Antineoplásicos , Melanoma , Síndromes Mielodisplásicos , Células Supresoras de Origen Mieloide , Animales , Anticuerpos Biespecíficos/farmacología , Antineoplásicos/farmacología , Humanos , Melanoma/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Lectina 3 Similar a Ig de Unión al Ácido Siálico , Linfocitos TRESUMEN
Myelodysplastic Syndromes (MDSs) are bone marrow (BM) failure malignancies characterized by constitutive innate immune activation, including NLRP3 inflammasome driven pyroptotic cell death. We recently reported that the danger-associated molecular pattern (DAMP) oxidized mitochondrial DNA (ox-mtDNA) is diagnostically increased in MDS plasma although the functional consequences remain poorly defined. We hypothesized that ox-mtDNA is released into the cytosol, upon NLRP3 inflammasome pyroptotic lysis, where it propagates and further enhances the inflammatory cell death feed-forward loop onto healthy tissues. This activation can be mediated via ox-mtDNA engagement of Toll-like receptor 9 (TLR9), an endosomal DNA sensing pattern recognition receptor known to prime and activate the inflammasome propagating the IFN-induced inflammatory response in neighboring healthy hematopoietic stem and progenitor cells (HSPCs), which presents a potentially targetable axis for the reduction in inflammasome activation in MDS. We found that extracellular ox-mtDNA activates the TLR9-MyD88-inflammasome pathway, demonstrated by increased lysosome formation, IRF7 translocation, and interferon-stimulated gene (ISG) production. Extracellular ox-mtDNA also induces TLR9 redistribution in MDS HSPCs to the cell surface. The effects on NLRP3 inflammasome activation were validated by blocking TLR9 activation via chemical inhibition and CRISPR knockout, demonstrating that TLR9 was necessary for ox-mtDNA-mediated inflammasome activation. Conversely, lentiviral overexpression of TLR9 sensitized cells to ox-mtDNA. Lastly, inhibiting TLR9 restored hematopoietic colony formation in MDS BM. We conclude that MDS HSPCs are primed for inflammasome activation via ox-mtDNA released by pyroptotic cells. Blocking the TLR9/ox-mtDNA axis may prove to be a novel therapeutic strategy for MDS.
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ADN Mitocondrial , Inflamasomas , Síndromes Mielodisplásicos , Receptor Toll-Like 9 , Humanos , ADN Mitocondrial/metabolismo , Inflamasomas/metabolismo , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Transducción de Señal/fisiología , Receptor Toll-Like 9/metabolismoRESUMEN
Somatic gene mutations are key determinants of outcome in patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). In particular, patients with TP53 mutations represent a distinct molecular cohort with uniformly poor prognosis. The precise pathogenetic mechanisms underlying these inferior outcomes have not been delineated. In this study, we characterized the immunological features of the malignant clone and alterations in the immune microenvironment in patients with TP53-mutant and wild-type MDS or sAML. Notably, PDL1 expression is significantly increased in hematopoietic stem cells of patients with TP53 mutations, which is associated with MYC upregulation and marked downregulation of MYC's negative regulator miR-34a, a p53 transcription target. Notably, patients with TP53 mutations display significantly reduced numbers of bone marrow-infiltrating OX40+ cytotoxic T cells and helper T cells, as well as decreased ICOS+ and 4-1BB+ natural killer cells. Further, highly immunosuppressive regulatory T cells (Tregs) (ie, ICOShigh/PD-1-) and myeloid-derived suppressor cells (PD-1low) are expanded in cases with TP53 mutations. Finally, a higher proportion of bone marrow-infiltrating ICOShigh/PD-1- Treg cells is a highly significant independent predictor of overall survival. We conclude that the microenvironment of TP53 mutant MDS and sAML has an immune-privileged, evasive phenotype that may be a primary driver of poor outcomes and submit that immunomodulatory therapeutic strategies may offer a benefit for this molecularly defined subpopulation.
Asunto(s)
Leucemia Mieloide Aguda , Mutación , Síndromes Mielodisplásicos , Células Supresoras de Origen Mieloide/inmunología , Linfocitos T Reguladores/inmunología , Proteína p53 Supresora de Tumor , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Terapia de Inmunosupresión , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Masculino , MicroARNs/genética , MicroARNs/inmunología , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/patología , Células Supresoras de Origen Mieloide/patología , ARN Neoplásico/genética , ARN Neoplásico/inmunología , Linfocitos T Reguladores/patología , Proteína p53 Supresora de Tumor/inmunologíaRESUMEN
Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap disorders characterized by monocytosis, myelodysplasia, and a characteristic hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Currently, there are no available disease-modifying therapies for CMML, nor are there preclinical models that fully recapitulate the unique features of CMML. Through use of immunocompromised mice with transgenic expression of human GM-CSF, interleukin-3, and stem cell factor in a NOD/SCID-IL2Rγnull background (NSGS mice), we demonstrate remarkable engraftment of CMML and JMML providing the first examples of serially transplantable and genetically accurate models of CMML. Xenotransplantation of CD34+ cells (n = 8 patients) or unfractionated bone marrow (BM) or peripheral blood mononuclear cells (n = 10) resulted in robust engraftment of CMML in BM, spleen, liver, and lung of recipients (n = 82 total mice). Engrafted cells were myeloid-restricted and matched the immunophenotype, morphology, and genetic mutations of the corresponding patient. Similar levels of engraftment were seen upon serial transplantation of human CD34+ cells in secondary NSGS recipients (2/5 patients, 6/11 mice), demonstrating the durability of CMML grafts and functionally validating CD34+ cells as harboring the disease-initiating compartment in vivo. Successful engraftments of JMML primary samples were also achieved in all NSGS recipients (n = 4 patients, n = 12 mice). Engraftment of CMML and JMML resulted in overt phenotypic abnormalities and lethality in recipients, which facilitated evaluation of the JAK2/FLT3 inhibitor pacritinib in vivo. These data reveal that NSGS mice support the development of CMML and JMML disease-initiating and mature leukemic cells in vivo, allowing creation of genetically accurate preclinical models of these disorders.
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Hidrocarburos Aromáticos con Puentes/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielomonocítica Juvenil/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Pirimidinas/farmacología , Animales , Femenino , Xenoinjertos , Humanos , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/metabolismo , Leucemia Mielomonocítica Juvenil/patología , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/patología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Trasplante de Neoplasias , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
A genetically inspired prognostic scoring system (GIPSS) that stratifies primary myelofibrosis (PMF) patients by genetic variants alone was recently proposed. While non-inferior to the dynamic international prognostic scoring system (DIPSS), the lack of overlapping prognostic variables between the models leads to increased risk for disagreement between two valid prognostic models and presents a challenging clinical situation. In an external cohort of 266 molecularly annotated myelofibrosis (MF) patients, we demonstrated that the GIPSS model significantly differentiated between four risk groups (low, int-1, int-2, high) with median OS that was not reached, not reached, 60.5 and 28.9 months, respectively. High-risk patients had significantly inferior leukemia-free survival (LFS) (P < 0.0001). We identified a cohort of prognostically ambiguous patients (n = 39) in which GIPSS and DIPSS models differed by ≥2 risk groups. Among these patients, a similar proportion were up-staged by DIPSS (n = 19) and GIPSS (n = 20). Patients upstaged by GIPSS (genetically high-risk) had a trend toward inferior OS compared with patients upstaged by DIPSS (clinically high-risk) (P = .08) and significantly worse LFS (P = .04). Patients deemed intermediate-2 and high-risk by GIPSS who underwent allogeneic transplant had improved OS compared with those that did not (P = .04). GIPSS is a valid disease-specific prognostic system and outperforms DIPSS in patients where the two models disagree. Additionally, while GIPSS was developed for PMF; the current study shows, however, that the contemporary genetic model performs equally well for both primary and secondary myelofibrosis.
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Mutación , Mielofibrosis Primaria/genética , Índice de Severidad de la Enfermedad , Anciano , Aloinjertos , Biopsia , Médula Ósea/patología , Calreticulina/genética , ADN/genética , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Janus Quinasa 2/genética , Estimación de Kaplan-Meier , Masculino , Policitemia Vera/complicaciones , Mielofibrosis Primaria/mortalidad , Mielofibrosis Primaria/terapia , Pronóstico , Receptores de Trombopoyetina/genética , Medición de Riesgo , Trombocitemia Esencial/complicacionesRESUMEN
Exome sequencing studies in chronic myelomonocytic leukemia (CMML) illustrate a mutational landscape characterized by few somatic mutations involving a subset of recurrent gene mutations in ASXL1, SRSF2, and TET2, each approaching 40% in incidence. This has led to the clinical implementation of next-generation sequencing panels that effectively identify clonal monocytosis and complement clinical prognostic scoring systems in most patients. However, most murine models based on single gene mutations fail to recapitulate the CMML phenotype, and many gene mutations are loss of function, making the identification of traditional therapeutic vulnerabilities challenging. Further, as a subtype of the myelodysplastic/myeloproliferative neoplasms, CMML has a complex clinical heterogeneity not reflected by the mutational landscape. In this review, we will discuss the discordance between mutational homogeneity and clinical complexity and highlight novel genomic and nongenomic approaches that offer insight into the underlying clinical characteristics of CMML.
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Heterogeneidad Genética , Leucemia Mielomonocítica Crónica/clasificación , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/patología , Mutación , Progresión de la Enfermedad , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Fenotipo , PronósticoRESUMEN
Despite genetic heterogeneity, myelodysplastic syndromes (MDSs) share features of cytological dysplasia and ineffective hematopoiesis. We report that a hallmark of MDSs is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins and manifest activated NLRP3 complexes that direct activation of caspase-1, generation of interleukin-1ß (IL-1ß) and IL-18, and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX), increasing levels of reactive oxygen species (ROS) that initiate cation influx, cell swelling, and ß-catenin activation. Notably, knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear ß-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus, alarmins and founder gene mutations in MDSs license a common redox-sensitive inflammasome circuit, which suggests new avenues for therapeutic intervention.
Asunto(s)
Inflamasomas/metabolismo , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/patología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Calgranulina B/metabolismo , Tamaño de la Célula , Ensayo de Unidades Formadoras de Colonias , Hematopoyesis , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Humanos , Activación del Canal Iónico , Canales Iónicos/metabolismo , Ratones Transgénicos , Mutación/genética , NADPH Oxidasas/metabolismo , Fenotipo , Piroptosis , Especies Reactivas de Oxígeno/metabolismo , beta Catenina/metabolismoRESUMEN
The prognostic value of peripheral blasts (PB) is not well-studied in patients with myelodysplastic syndromes (MDS). We evaluated the impact of PB on overall survival (OS) and transformation to acute myeloid leukemia (AML) in a large cohort. The MDS database at the Moffitt Cancer Center was retrospectively reviewed to identify patients with ≥ 1% PB (PB-MDS) and those without PB (BM-MDS). We also assessed the correlation between PB and gene mutations. One thousand seven hundred fifty-eight patients were identified, among whom 13% had PB near the time of diagnosis. PB-MDS patients were more likely to be younger with trilineage cytopenia, complex karyotype, higher-risk disease, transfusion dependence, and therapy-related MDS. The rate of AML transformation was 49 vs. 26% (p < 0.005) and median OS was 16.5 vs. 45.8 months (p < 0.005) in the PB-MDS and BM-MDS groups, respectively. In Cox regression analysis, the presence of PB was an independent prognostic covariate for OS, HR 1.57 (95% CI 1.2-2). Among 51 patients with an available gene panel, the rate of ≥ 1 gene mutation in the PB-MDS group (n = 4) was 100% compared to 81% in the BM-MDS group (n = 47). The presence of PB in MDS is an adverse independent prognostic variable that refines prognostic discrimination.
Asunto(s)
Células de la Médula Ósea/patología , Leucemia Mieloide Aguda/diagnóstico , Síndromes Mielodisplásicos/diagnóstico , Proteínas de Neoplasias/genética , Anciano , Anciano de 80 o más Años , Células de la Médula Ósea/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Cariotipo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Mutación , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología , Células Neoplásicas Circulantes , Pronóstico , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
Ruxolitinib is a JAK1/2 inhibitor that is effective in managing symptoms and splenomegaly related to myelofibrosis (MF). Unfortunately, many patients must discontinue ruxolitinib, at which time treatment options are not well defined. In this study, we investigated salvage treatment options and clinical outcomes among MF patients who received and discontinued ruxolitinib outside the context of a clinical trial. Among 145 patients who received ruxolitinib, 23 died while on treatment, 58 remained on treatment at time of analysis, leaving 64 people available for analysis. Development of cytopenias was the most common reason for discontinuation (38%) after median treatment time of 3.8 months (mo). The majority of patients received some form of salvage therapy after ruxolitinib discontinuation (n = 42; 66%), with allogeneic hematopoietic stem cell transplant (alloHSCT) (n = 17), being most commonly employed. Lenalidomide, thalidomide, hydroxyurea, interferon, and danazol were used with similar frequency. The response rate to salvage treatment was 26% (8 responses) and responses were most often seen with lenalidomide or thalidomide. Improved outcomes were observed in patients who underwent alloHSCT or received salvage therapy compared to those who did not receive additional therapy. Median overall survival (OS) after ruxolitinib discontinuation was 13 months. These findings show that salvage therapy can provide clinical responses after ruxolitinib discontinuation; however, these responses are rare and outcomes in this patient population are poor. This represents an area of unmet clinical need in MF.
Asunto(s)
Mielofibrosis Primaria/tratamiento farmacológico , Pirazoles/uso terapéutico , Privación de Tratamiento , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Cuidados Paliativos , Mielofibrosis Primaria/complicaciones , Mielofibrosis Primaria/mortalidad , Mielofibrosis Primaria/terapia , Pirimidinas , Estudios Retrospectivos , Terapia Recuperativa , Esplenomegalia/tratamiento farmacológico , Esplenomegalia/etiología , Esplenomegalia/mortalidad , Análisis de Supervivencia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Loss or deletion of chromosome 7 is commonly seen in MDS and leads to a poor prognosis. However, the identity of functionally relevant, dysplasia-causing, genes on 7q remains unclear. Dedicator of cytokinesis 4 (DOCK4) is a GTPase exchange factor, and its gene maps to the commonly deleted 7q region. We demonstrate that DOCK4 is underexpressed in MDS bone marrow samples and that the reduced expression is associated with decreased overall survival in patients. We show that depletion of DOCK4 levels leads to erythroid cells with dysplastic morphology both in vivo and in vitro. We established a novel single-cell assay to quantify disrupted F-actin filament network in erythroblasts and demonstrate that reduced expression of DOCK4 leads to disruption of the actin filaments, resulting in erythroid dysplasia that phenocopies the red blood cell (RBC) defects seen in samples from MDS patients. Reexpression of DOCK4 in -7q MDS patient erythroblasts resulted in significant erythropoietic improvements. Mechanisms underlying F-actin disruption revealed that DOCK4 knockdown reduces ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase activation, leading to increased phosphorylation of the actin-stabilizing protein ADDUCIN in MDS samples. These data identify DOCK4 as a putative 7q gene whose reduced expression can lead to erythroid dysplasia.
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Eritroblastos/metabolismo , Proteínas Activadoras de GTPasa/biosíntesis , Regulación de la Expresión Génica , Síndromes Mielodisplásicos/metabolismo , Actinas/genética , Actinas/metabolismo , Animales , Proteínas de Unión a Calmodulina/genética , Proteínas de Unión a Calmodulina/metabolismo , Eritroblastos/patología , Femenino , Proteínas Activadoras de GTPasa/genética , Humanos , Masculino , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Proteína de Unión al GTP rac1/genética , Proteína de Unión al GTP rac1/metabolismoRESUMEN
BACKGROUND: Clonal haemopoiesis of indeterminate potential (CHIP) is an age-associated genetic event linked to increased risk of primary haematological malignancies and increased all-cause mortality, but the prevalence of CHIP in patients who develop therapy-related myeloid neoplasms is unknown. We did this study to investigate whether chemotherapy-treated patients with cancer who have CHIP are at increased risk of developing therapy-related myeloid neoplasms. METHODS: We did a nested, case-control, proof-of-concept study to compare the prevalence of CHIP between patients with cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not develop these neoplasms (controls). We identified cases from our internal biorepository of 123â357 patients who consented to participate in the Total Cancer Care biobanking protocol at Moffitt Cancer Center (Tampa, FL, USA) between Jan 1, 2006, and June 1, 2016. We included all individuals who were diagnosed with a primary malignancy, were treated with chemotherapy, subsequently developed a therapy-related myeloid neoplasm, and were 70 years or older at either diagnosis. For inclusion in this study, individuals must have had a peripheral blood or mononuclear cell sample collected before the diagnosis of therapy-related myeloid neoplasm. Controls were individuals who were diagnosed with a primary malignancy at age 70 years or older and were treated with chemotherapy but did not develop therapy-related myeloid neoplasms. Controls were matched to cases in at least a 4:1 ratio on the basis of sex, primary tumour type, age at diagnosis, smoking status, chemotherapy drug class, and duration of follow-up. We used sequential targeted and whole-exome sequencing and described clonal evolution in cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available. The primary endpoint of this study was the development of therapy-related myeloid neoplasm and the primary exposure was CHIP. FINDINGS: We identified 13 cases and 56 case-matched controls. The prevalence of CHIP in all patients (23 [33%] of 69 patients) was higher than has previously been reported in elderly individuals without cancer (about 10%). Cases had a significantly higher prevalence of CHIP than did matched controls (eight [62%] of 13 cases vs 15 [27%] of 56 controls, p=0·024; odds ratio 5·75, 95% CI 1·52-25·09, p=0·013). The most commonly mutated genes in cases with CHIP were TET2 (three [38%] of eight patients) and TP53(three [38%] of eight patients), whereas controls most often had TET2 mutations (six [40%] of 15 patients). In most (four [67%] of six patients) cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available, the mean allele frequency of CHIP mutations had expanded by the time of the therapy-related myeloid neoplasm diagnosis. However, a subset of paired samples (two [33%] of six patients) had CHIP mutations that decreased in allele frequency, giving way to expansion of a distinct mutant clone. INTERPRETATION: Patients with cancer who have CHIP are at increased risk of developing therapy-related myeloid neoplasms. The distribution of CHIP-related gene mutations differs between individuals with therapy-related myeloid neoplasm and those without, suggesting that mutation-specific differences might exist in therapy-related myeloid neoplasm risk. FUNDING: Moffitt Cancer Center.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/genética , Células Clonales/patología , Hematopoyesis/genética , Leucemia Mieloide Aguda/diagnóstico , Síndromes Mielodisplásicos/diagnóstico , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Células Clonales/efectos de los fármacos , Células Clonales/metabolismo , Femenino , Florida/epidemiología , Estudios de Seguimiento , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Incidencia , Leucemia Mieloide Aguda/inducido químicamente , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Mutación/genética , Síndromes Mielodisplásicos/inducido químicamente , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/genética , Estadificación de Neoplasias , Neoplasias/patología , Neoplasias Primarias Secundarias/inducido químicamente , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/genética , Pronóstico , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are hematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes and myeloproliferative neoplasms. There are currently no standard treatment recommendations for most adult patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic end points and standardized response criteria for clinical trials. The dual dysplastic and proliferative features in these stem cell malignancies define their uniqueness and challenges. We propose response assessment guidelines to harmonize future clinical trials with the principal objective of establishing suitable treatment algorithms. An international panel comprising laboratory and clinical experts in MDS/MPN was established involving 3 independent academic MDS/MPN workshops (March 2013, December 2013, and June 2014). These recommendations are the result of this collaborative project sponsored by the MDS Foundation.
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Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/terapia , Hematología/normas , Oncología Médica/normas , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/terapia , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/terapia , Algoritmos , Proliferación Celular , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Humanos , Cooperación Internacional , Mutación , Fenotipo , Guías de Práctica Clínica como Asunto , Encuestas y Cuestionarios , Resultado del TratamientoAsunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacocinética , Antineoplásicos Inmunológicos/administración & dosificación , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/farmacocinética , Quimioterapia Adyuvante , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/sangre , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/inmunología , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Humanos , Leucemia Mielomonocítica Crónica/metabolismo , Leucemia Mielomonocítica Crónica/terapia , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/farmacocinética , Resultado del TratamientoAsunto(s)
Eritropoyetina , Síndromes Mielodisplásicos , Biomarcadores , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Eritropoyetina/uso terapéutico , Humanos , Lenalidomida/uso terapéutico , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genéticaRESUMEN
In patients with acute myeloid leukemia (AML), the presence of residual disease at day 14 after primary induction therapy warrants consideration of a second induction cycle. However, data to guide retreatment decisions in such patients are presently limited. Here, we retrospectively reviewed data from 176 patients with AML treated at our institution with a second induction chemotherapy regimen because of day 14 residual disease. Clinical variables and nadir bone marrow features were assessed for correlations with complete remission (CR) and overall survival (OS). In our patient group, 59% achieved CR after a second induction course. Median OS for the entire group was 12.40 months (95% CI, 9.90-14.90) but 19.07 months (95% CI, 13.13-25.01) for those who attained a CR. Nadir marrow hypocellularity (P < 0.001) at day 14, absolute blast reduction of >50% (P = 0.030), and de novo disease status (P = 0.018) were significantly correlated with CR achievement after re-induction. Marrow hypocellularity at day 14 was the most significant predictor of CR on multivariate analysis (P < 0.001). Nadir marrow features did not independently correlate with OS when accounting for CR status. Re-induction was successful in achieving CR in most patients. Study patients who did not achieve CR were more likely to have nonhypocellular marrows.
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Células de la Médula Ósea/patología , Quimioterapia de Inducción/métodos , Leucemia Mieloide Aguda/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Examen de la Médula Ósea , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Inducción de Remisión/métodos , Retratamiento , Estudios Retrospectivos , Tasa de Supervivencia , Factores de Tiempo , Adulto JovenRESUMEN
The myelodysplastic syndromes (MDSs) include a spectrum of stem cell malignancies characterized by an increased risk of developing acute myeloid leukemia. Heterozygous loss of chromosome 5q (del[5q]) is the most common cytogenetic abnormality in MDS. DIAPH1 is localized to 5q31 and encodes one of the formin proteins, mDia1, which is involved in linear actin polymerization. Mice with mDia1 deficiency develop hematologic features with age mimicking human myeloid neoplasm, but its role in the pathogenesis of MDS is unclear. Here we report that mDia1 heterozygous and knockout mice develop MDS phenotypes with age. In these mice, CD14 was aberrantly overexpressed on granulocytes in a cell-autonomous manner, leading to a hypersensitive innate immune response to lipopolysaccharide (LPS) stimuli through CD14/Toll-like receptor 4 signaling. Chronic stimulation with LPS accelerated the development of MDS in mDia1 heterozygous and knockout mice that can be rescued by lenalidomide. Similar findings of CD14 overexpression were observed on the bone marrow granulocytes of del(5q) MDS patients. Mechanistically, mDia1 deficiency led to a downregulation of membrane-associated genes and a specific upregulation of CD14 messenger RNA in granulocytes, but not in other lineages. These results underscore the significance of mDia1 heterozygosity in deregulated innate immune responses in del(5q) MDS.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Portadoras/metabolismo , Deleción Cromosómica , Cromosomas Humanos Par 5 , Regulación de la Expresión Génica , Granulocitos/metabolismo , Heterocigoto , Inmunidad Innata , Receptores de Lipopolisacáridos/biosíntesis , Síndromes Mielodisplásicos/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/inmunología , Animales , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Proteínas Portadoras/genética , Proteínas Portadoras/inmunología , Femenino , Forminas , Granulocitos/inmunología , Granulocitos/patología , Humanos , Receptores de Lipopolisacáridos/genética , Receptores de Lipopolisacáridos/inmunología , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Noqueados , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/patología , ARN Mensajero/genética , ARN Mensajero/inmunología , ARN Mensajero/metabolismo , Receptor Toll-Like 4/agonistas , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología , Receptor Toll-Like 4/metabolismoRESUMEN
Disease-specific measures of quality of life can improve assessment of disease-related symptoms and psychosocial sequelae. We report on the development and validation of the Quality of Life in Myelodysplasia Scale (QUALMS), a 38-item assessment tool for patients with myelodysplastic syndromes (MDS). In 2014-2015, a multi-center cohort of patients with myelodysplasia completed the QUALMS, as well as the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and the Functional Assessment of Cancer Therapy Anemia Scale (FACT-An); a second administration was undertaken three to six months later. A total of 255 patients from the United States, Canada and Italy participated. Median age was 72 years, 56.1% were men, and the International Prognostic Scoring System distribution was 40.4% low, 42.0% intermediate-1, 13.3% intermediate-2 and 2.3% high. QUALMS scores ranged from 24 to 99 (higher scores are better), with a mean of 67.2 [standard deviation (SD)=15.2]. The measure was internally consistent (α=0.92), and moderately correlated with the multi-item QLQ-C30 scales and the FACT-An (r=-0.65 to 0.79; all P<0.001). Patients with hemoglobin of 8 g/dL or under scored lower than those with hemoglobin over 10 g/dL (61.8 vs 71.1; P<0.001), and transfusion-dependent patients scored lower than transfusion-independent patients (62.4 vs 69.7; P<0.01). Principal components analysis revealed "physical burden", "benefit-finding", and "emotional burden" subscales. There was good overall test-retest reliability among those with stable hemoglobin (r=0.81), and significant changes for patients hospitalized or with infections between administrations (both P<0.01). These data suggest the QUALMS is a valuable tool for assessing MDS-specific quality of life in the modern treatment era.
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Síndromes Mielodisplásicos/epidemiología , Vigilancia de la Población , Calidad de Vida , Adulto , Anciano , Anciano de 80 o más Años , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/psicología , Síndromes Mielodisplásicos/terapia , Psicometría , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Immune dysregulation and altered T-cell hemostasis play important roles in the pathogenesis of myelodysplastic syndromes (MDS). Recent studies suggest an increased risk of MDS among patients with autoimmune diseases. Here, we investigated the prevalence of autoimmune diseases among MDS patients, comparing characteristics and outcomes in those with and without autoimmune diseases. From our study group of 1408 MDS patients, 391 (28%) had autoimmune disease, with hypothyroidism being the most common type, accounting for 44% (n = 171) of patients (12% among all MDS patients analyzed). Other autoimmune diseases with ≥5% prevalence included idiopathic thrombocytopenic purpura in 12% (n = 46), rheumatoid arthritis in 10% (n = 41), and psoriasis in 7% (n = 28) of patients. Autoimmune diseases were more common in female MDS patients, those with RA or RCMD WHO subtype, and those who were less dependent on red blood cell transfusion. Median overall survival (OS) was 60 months (95% CI, 50-70) for patients with autoimmune diseases versus 45 months (95% CI, 40-49) for those without (log-rank test, P = 0.006). By multivariate analysis adjusting for revised IPSS and age >60 years, autoimmune diseases were a statistically significant independent factor for OS (HR 0.78; 95% CI, 0.66-0.92; P = 0.004). The rate of acute myeloid leukemia (AML) transformation was 23% (n = 89) in MDS patients with autoimmune disease versus 30% (n = 301) in those without (P = 0.011). Patient groups did not differ in response to azacitidine or lenalidomide treatment. Autoimmune diseases are prevalent among MDS patients. MDS patients with autoimmune diseases have better OS and less AML transformation.