RESUMEN
ABSTRACT: Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing. Sixteen novel mutational targets were identified in ML-DS samples. Of these, inactivations of IRX1 (16.2%) and ZBTB7A (13.2%) were commonly implicated in the upregulation of the MYC pathway and were potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors. Partial tandem duplications of RUNX1 on chromosome 21 were also found, specifically in ML-DS samples (13.7%), presenting its essential role in DS leukemia progression. Finally, in 177 patients with ML-DS treated following the same ML-DS protocol (the Japanese Pediatric Leukemia and Lymphoma Study Group acute myeloid leukemia -D05/D11), CDKN2A, TP53, ZBTB7A, and JAK2 alterations were associated with a poor prognosis. Patients with CDKN2A deletions (n = 7) or TP53 mutations (n = 4) had substantially lower 3-year event-free survival (28.6% vs 90.5%; P < .001; 25.0% vs 89.5%; P < .001) than those without these mutations. These findings considerably change the mutational landscape of ML-DS, provide new insights into the mechanisms of progression from TAM to ML-DS, and help identify new therapeutic targets and strategies for ML-DS.
Asunto(s)
Síndrome de Down , Mutación , Humanos , Síndrome de Down/genética , Síndrome de Down/complicaciones , Masculino , Femenino , Reacción Leucemoide/genética , Lactante , Preescolar , Secuenciación del Exoma , Pronóstico , Leucemia Mieloide/genética , Recién Nacido , Niño , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genéticaRESUMEN
Here, we describe two patients with juvenile xanthogranuloma (JXG) manifesting with Langerhans cell histiocytosis (LCH)-associated neurodegenerative disease (ND)-like radiological findings. One patient showed typical radiological abnormalities at onset, which worsened with progressing central nervous system symptoms 7 years after LCH-oriented chemotherapy. Another showed spontaneous regression of clinical symptoms, with a transient radiological change 1 year after salvage chemotherapy for recurrence of JXG. These data regarding JXG-associated ND will facilitate future investigation of the disease, as well as development of therapeutic interventions.
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Histiocitosis de Células de Langerhans , Enfermedades Neurodegenerativas , Xantogranuloma Juvenil , Niño , Humanos , Lactante , Masculino , Histiocitosis de Células de Langerhans/diagnóstico por imagen , Histiocitosis de Células de Langerhans/patología , Histiocitosis de Células de Langerhans/complicaciones , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Imagen por Resonancia Magnética , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/complicaciones , Xantogranuloma Juvenil/diagnóstico por imagen , Xantogranuloma Juvenil/patologíaRESUMEN
Diamond-Blackfan anemia (DBA) is a congenital anemia with erythroid cell aplasia. Most of the causative genes are ribosomal proteins. GATA1, a hematopoietic master transcription factor required for erythropoiesis, also causes DBA. GATA1 is located on Xp11.23; therefore, DBA develops only in males in an X-linked inheritance pattern. Here, we report a case of transient erythroblastopenia and moderate anemia in a female newborn infant with a de novo GATA1 variant. In this patient, increased methylation of the GATA1 wild-type allele was observed in erythroid cells. Skewed lyonization of GATA1 may cause mild transient erythroblastopenia in a female patient.
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Anemia Aplásica , Anemia de Diamond-Blackfan , Anemia Hemolítica Congénita , Masculino , Lactante , Recién Nacido , Humanos , Femenino , Proteínas Ribosómicas/genética , Anemia de Diamond-Blackfan/genética , Eritropoyesis , Factor de Transcripción GATA1/genéticaRESUMEN
Histiocytoses, including Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD), are inflammatory myeloid tumors in which monocyte lineage cells aggregate in various organs, causing tissue damage. Most of these tumors harbor oncogenic mutations in mitogen-activated protein kinase (MAPK) pathway genes, typified by BRAFV600E. Some patients with LCH develop bilateral symmetrical cerebellar lesions and brain atrophy several years after diagnosis when the initial symptoms disappear, leading to cerebellar ataxia and higher cerebral dysfunction. A similar neurological disorder has also been reported in ECD. This neurological disorder can be improved with MAPK inhibitors. When patients with this neurological disorder are identified among neurodegeneration of unknown etiology or histiocytosis patients and treated early with MAPK inhibitors, the disorder can be reversible.
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Encefalopatías , Enfermedad de Erdheim-Chester , Histiocitosis de Células de Langerhans , Neoplasias , Humanos , Histiocitosis de Células de Langerhans/diagnóstico , Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/patología , Enfermedad de Erdheim-Chester/diagnóstico , Enfermedad de Erdheim-Chester/genética , Enfermedad de Erdheim-Chester/patología , MutaciónRESUMEN
Myeloid leukemia associated with Down syndrome (ML-DS) responds well to chemotherapy and has a favorable prognosis, but the clinical outcome of patients with refractory or relapsed ML-DS is dismal. We recently reported a case of relapsed ML-DS with an effective response to a DNA methyltransferase inhibitor, azacitidine (AZA). However, the efficacy of AZA for refractory or relapsed ML-DS remains uncertain. Here, we investigated the effects and mechanism of action of AZA on three ML-DS cell lines derived from relapsed cases. AZA inhibited the proliferation of all examined ML-DS cell lines to the same extent as that of AZA-sensitive acute myeloid leukemia non-Down syndrome cell lines. Transient low-dose AZA treatment exerted durable antileukemic effects on ML-DS cells. The inhibitory effect included cell cycle arrest, apoptosis, and reduction of aldehyde dehydrogenase activity. Comprehensive differential gene expression analysis showed that AZA induced megakaryocytic differentiation in all ML-DS cell lines examined. Furthermore, AZA induced activation of type I interferon-stimulated genes, primarily involved in antiproliferation signaling, without stimulation of the interferon receptor-mediated autocrine system. Activation of the type I interferon pathway by stimulation with interferon-α exerted antiproliferative effects on ML-DS cells, suggesting that AZA exerts its antileukemic effects on ML-DS cells at least partially through the type I interferon pathway. Moreover, the effect of AZA on normal hematopoiesis did not differ significantly between individuals with non-Down syndrome and Down syndrome. In summary, this study suggests that AZA is a potentially effective treatment option for ML-DS disease control, including relapsed cases, and has reduced side effects.
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Azacitidina , Síndrome de Down , Inhibidores Enzimáticos , Interferón Tipo I , Leucemia Mieloide Aguda , Humanos , Azacitidina/farmacología , Azacitidina/uso terapéutico , Línea Celular , ADN , Síndrome de Down/complicaciones , Síndrome de Down/tratamiento farmacológico , Síndrome de Down/genética , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , MetiltransferasasRESUMEN
INTRODUCTION: Although the prognosis of Langerhans cell histiocytosis (LCH) is excellent, the high recurrence rate and permanent consequences, such as central diabetes insipidus and LCH-associated neurodegenerative diseases, remain to be resolved. Based on previous reports that patients with high-risk multisystem LCH show elevated levels of inflammatory molecules, we hypothesised that dexamethasone would more effectively suppress LCH-associated inflammation, especially in the central nervous system (CNS). We further hypothesised that intrathecal chemotherapy would effectively reduce CNS complications. We administer zoledronate to patients with multifocal bone LCH based on an efficacy report from a small case series. METHODS AND ANALYSIS: This phase II study (labelled the LCH-19-MSMFB study) is designed to evaluate the significance of introducing dexamethasone and intrathecal chemotherapy for multisystem disease and zoledronate for multifocal bone disease in previously untreated, newly diagnosed children, adolescents (under 20 years) and adults under 40 years. The primary endpoint is the 3-year event-free survival rate by risk group of under 20 years and the 3-year event-free survival rate of 20 years and over. ETHICS AND DISSEMINATION: This study was approved by the Central Review Board of the National Hospital Organisation Nagoya Medical Centre (Nagoya, Japan) on 21 January 2022 and was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp/en-latest-detail/jRCTs041210027). Written informed consent will be obtained from all patients and/or their guardians. TRIAL REGISTRATION NUMBER: jRCTs041210027.
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Dexametasona , Histiocitosis de Células de Langerhans , Ácido Zoledrónico , Humanos , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Histiocitosis de Células de Langerhans/diagnóstico , Histiocitosis de Células de Langerhans/mortalidad , Niño , Adolescente , Japón , Adulto , Dexametasona/uso terapéutico , Dexametasona/administración & dosificación , Adulto Joven , Ácido Zoledrónico/uso terapéutico , Masculino , Femenino , Ensayos Clínicos Fase II como Asunto , Preescolar , Conservadores de la Densidad Ósea/uso terapéuticoRESUMEN
When Epstein-Barr virus (EBV) infection is suspected, identification of infected cells is important to understand the pathogenesis, determinine the treatment strategy, and predict the prognosis. We used the PrimeFlow™ RNA Assay Kit with a probe to detect EBV-encoded small RNAs (EBERs) and multiple surface markers, to identify EBV-infected cells by flow cytometry. We analyzed a total of 24 patients [11 with chronic active EBV disease (CAEBV), 3 with hydroa vacciniforme lymphoproliferative disorder, 2 with X-linked lymphoproliferative disease type 1 (XLP1), 2 with EBV-associated hemophagocytic lymphohistiocytosis, and 6 with posttransplant lymphoproliferative disorder (PTLD)]. We compared infected cells using conventional quantitative PCR methods and confirmed that infected cell types were identical in most patients. Patients with CAEBV had widespread infection in T and NK cells, but a small amount of B cells were also infected, and infection in patients with XLP1 and PTLD was not limited to B cells. EBV-associated diseases are believed to be complex pathologies caused by EBV infecting a variety of cells other than B cells. We also demonstrated that infected cells were positive for HLA-DR in patients with CAEBV. EBER flow FISH can identify EBV-infected cells with high sensitivity and is useful for elucidating the pathogenesis.