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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.
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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
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
BACKGROUND: Langerhans cell histiocytosis (LCH) was previously characterized as the proliferation of Langerhans-type histiocytes with a wide range of clinical presentations that arise mostly in children. The typical presentation is a gradually enlarging, painless skull mass. Rapid clinical deterioration is rare. OBSERVATIONS: A 3-year-old boy who had incurred a right frontal impact head injury demonstrated no apparent neurological deficits. He subsequently bruised the same region multiple times. The right frontal swelling gradually increased over the course of 6 days after the initial injury. Skull radiography showed no bony lesion. The same site enlarged markedly 12 days after the initial injury. Magnetic resonance imaging revealed a frontal bony tumorous lesion associated with multiple subcutaneous cystic mass lesions. The patient underwent open biopsy of the skull lesion and evacuation of the subcutaneous lesions. Histopathological examination confirmed the diagnosis of LCH. Immunohistochemical evaluation revealed positivity for CD1a and langerin and no immunopositivity for BRAF V600E. The skull lesion spontaneously disappeared 30 days after the biopsy without recurrence. LESSONS: Physicians should be aware of this rare clinical manifestation of LCH that developed by a repeat head injury.
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Children with Down syndrome (DS) are at high risk of transient abnormal myelopoiesis (TAM) and myeloid leukemia of DS (ML-DS). GATA1 mutations are detected in almost all TAM and ML-DS samples, with exclusive expression of short GATA1 protein (GATA1s) lacking the N-terminal domain (NTD). However, it remains to be clarified how GATA1s is involved with both disorders. Here, we established the K562 GATA1s (K562-G1s) clones expressing only GATA1s by CRISPR/Cas9 genome editing. The K562-G1s clones expressed KIT at significantly higher levels compared to the wild type of K562 (K562-WT). Chromatin immunoprecipitation studies identified the GATA1-bound regulatory sites upstream of KIT in K562-WT, K562-G1s clones and two ML-DS cell lines; KPAM1 and CMK11-5. Sonication-based chromosome conformation capture (3C) assay demonstrated that in K562-WT, the - 87 kb enhancer region of KIT was proximal to the - 115 kb, - 109 kb and + 1 kb region, while in a K562-G1s clone, CMK11-5 and primary TAM cells, the - 87 kb region was more proximal to the KIT transcriptional start site. These results suggest that the NTD of GATA1 is essential for proper genomic conformation and regulation of KIT gene expression, and that perturbation of this function might be involved in the pathogenesis of TAM and ML-DS.
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Síndrome de Down , Niño , Humanos , Línea Celular Tumoral , Síndrome de Down/genética , Factor de Transcripción GATA1/genética , Regulación de la Expresión Génica , OncogenesRESUMEN
Diamond-Blackfan anaemia (DBA) shares clinical features with two recently reported sporadic cases of dyserythropoietic anaemia with a cryptic GATA1 splicing mutation (c.871-24 C>T). We hypothesized that some patients clinically diagnosed with DBA but whose causative genes were unknown may carry the intronic GATA1 mutation. Here, we examined 79 patients in our DBA cohort, who had no detectable causative genes. The intronic GATA1 mutation was identified in two male patients sharing the same pedigree that included multiple cases with anaemia. Cosegregation of this mutation and disease in multiple family members provide evidence to support the pathogenicity of the intronic GATA1 mutation.
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Extraneural recurrence of a medulloblastoma is rare with dismal prognosis. A 9-year-old girl with medulloblastoma was treated with gross total resection followed by a combination of chemotherapy and radiotherapy. Fourteen months after treatment completion, she developed multifocal bone metastases. Despite chemotherapy combined with irradiation, she died 18 months after recurrence due to progressive disease. Fluorescence in situ hybridization on formalin-fixed paraffin-embedded tissue sections revealed MYCN amplification and TP53 loss, consistent with the genetic alterations of a rapidly progressive subgroup of recurrent medulloblastomas. In clinical practice, dismal biologic features can be determined using fluorescence in situ hybridization in defective materials.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , Neoplasias Encefálicas/patología , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/terapia , Niño , Femenino , Humanos , Hibridación Fluorescente in Situ , Meduloblastoma/genética , Meduloblastoma/patología , Meduloblastoma/terapia , Proteína Proto-Oncogénica N-Myc/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders characterized by bone marrow failure, congenital anomalies, and increased risk of malignant disease. Next generation sequencing methods have greatly facilitated the discovery of genetic etiology in IBMFS. Recently, de novo mutations activating TP53 were detected in patients with BMFS, mimicking Diamond-Blackfan anemia (DBA), using whole exome sequencing, and these patients were recognized as having a novel disorder. This discovery provides important insights into the previously postulated connection between p53 activation and IBMFS. Furthermore, a novel IBMFS, aldehyde degradation deficiency syndrome, was found in patients with aplastic anemia resembling Fanconi anemia (FA). This disorder is caused by combined inactivating mutations in ADH5 and ALDH2 coding formaldehyde-detoxifying enzymes. In this review, we highlight recent studies on DBA, FA, and their related diseases in Japan.
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Anemia Aplásica , Anemia de Diamond-Blackfan , Enfermedades de la Médula Ósea , Hemoglobinuria Paroxística , Aldehído Deshidrogenasa Mitocondrial , Anemia Aplásica/diagnóstico , Anemia Aplásica/genética , Anemia de Diamond-Blackfan/genética , Enfermedades de la Médula Ósea/genética , Trastornos de Fallo de la Médula Ósea , Síndromes Congénitos de Insuficiencia de la Médula Ósea , Hemoglobinuria Paroxística/diagnóstico , Hemoglobinuria Paroxística/genética , HumanosRESUMEN
Although thiopurine is a crucial drug for treating acute lymphoblastic leukemia, individual variations in intolerance are observed due to gene polymorphisms. A 3-year-old boy with B-cell precursor acute lymphoblastic leukemia who was administered thiopurine developed mucositis, sepsis, and hemophagocytic lymphohistiocytosis due to prolonged hematologic toxicity, chronic disseminated candidiasis, and infective endocarditis that triggered multiple brain infarctions. The patient was found to harbor 3 gene polymorphisms associated with thiopurine intolerance including homozygous NUDT15 R139C, heterozygous ITPA C94A, and homozygous MTHFR C677T and heterozygous RFC1 G80A. Thus, the combined effect of intolerance via multiple gene polymorphisms should be considered in case of unexpected adverse reactions.
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Hipersensibilidad a las Drogas/patología , Homocigoto , Mercaptopurina/efectos adversos , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pirofosfatasas/genética , Antimetabolitos Antineoplásicos , Infarto Encefálico/inducido químicamente , Infarto Encefálico/genética , Infarto Encefálico/patología , Preescolar , Hipersensibilidad a las Drogas/etiología , Humanos , Infecciones/inducido químicamente , Infecciones/genética , Infecciones/patología , Linfohistiocitosis Hemofagocítica/inducido químicamente , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/patología , Masculino , Mucositis/inducido químicamente , Mucositis/genética , Mucositis/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Sepsis/inducido químicamente , Sepsis/genética , Sepsis/patologíaRESUMEN
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations of Diamond-Blackfan anemia (DBA). However, data regarding the optimal conditioning regimen for DBA patients are limited. We retrospectively compared the outcomes of DBA patients who underwent HSCT using either myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) regimens. The patients belonged to a cohort treated at our hospitals between 2000 and 2018. HSCT was performed in 27 of 165 patients (16.4%). The median age at the time of HSCT was 3.6 years. Stem cell sources included bone marrow for 25 patients (HLA-matched sibling donors, n = 5; HLA-mismatched related donors, n = 2; HLA-matched/mismatched unrelated donors, n = 18) or cord blood for 2 patients. MAC or RIC regimens were used in 12 and 15 patients, respectively. Engraftment was successful in all 27 patients who underwent HSCT. Three patients who underwent HSCT using MAC regimens developed sinusoidal obstruction syndrome. The 3-year overall survival (OS) and failure-free survival rates (FFS) post-transplantations were 95.2% and 88.4%, respectively, with no significant differences between MAC and RIC regimens. Our data suggest that HSCTs using RIC regimens are effective and obtain engraftment with excellent OS and FFS for young DBA patients.
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Anemia de Diamond-Blackfan , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Anemia de Diamond-Blackfan/terapia , Niño , Humanos , Estudios Retrospectivos , Hermanos , Acondicionamiento PretrasplanteRESUMEN
BACKGROUND: The prognosis of patients with metastatic Ewing sarcoma family of tumors (ESFT) remains poor. PROCEDURE: We retrospectively analyzed 57 patients diagnosed with metastatic ESFT between 2000 and 2018 to identify prognostic and therapeutic factors affecting the clinical outcome. RESULTS: The 3-year overall survival (OS) rate of the entire cohort was 46.8% (95% confidence interval [CI], 33.0-59.4%). Treatment-related death was not observed. Multivariate analysis identified stem cell transplantation (SCT), response to first-line chemotherapy, and bone metastasis as independent risk factors for OS. Objective response rate to first-line chemotherapy was 65.1% in the 43 evaluable patients. There was no significant difference in the response to different types of first-line chemotherapy. Among patients with lung metastasis alone, the 3-year OS rate was higher in 13 patients who received local treatment than in four who did not, although the difference was not significant. CONCLUSIONS: One possible reason for the high OS rates was the absence of treatment-related mortality even in patients receiving SCT, which could be attributed to advances in the management of post-SCT complications. Novel first-line chemotherapy strategies need to be established to improve the disease status prior to SCT in a higher proportion of patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/mortalidad , Trasplante de Células Madre Hematopoyéticas/mortalidad , Neoplasias Pulmonares/mortalidad , Sarcoma de Ewing/mortalidad , Adolescente , Adulto , Neoplasias Óseas/patología , Neoplasias Óseas/terapia , Niño , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Masculino , Pronóstico , Estudios Retrospectivos , Sarcoma de Ewing/patología , Sarcoma de Ewing/terapia , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Transient abnormal myelopoiesis (TAM) is a unique myeloproliferative disorder that occurs in neonates with constitutional trisomy 21/Down syndrome (DS). Although TAM also develops in neonates without constitutional trisomy 21, the clinical, cytogenetic, and molecular characteristics of those patients are not fully understood. PROCEDURE: We retrospectively evaluated the clinical and cytogenetic findings and GATA1 mutation status of 17 neonates with TAM and nonconstitutional trisomy 21 tested for GATA1 mutations at our institute, and compared the findings with those of 64 neonates with TAM and constitutional trisomy 21/DS. RESULTS: DS clinical features were observed in five of the 17 (29%) patients. In all patients, both trisomy 21 and GATA1 mutations were detected in diagnostic samples. Over a median follow-up of 33 (range, 0-139) months, early death (< 6 months of age) occurred in four patients (24%). Overall and event-free survivals were not significantly different between the patients with TAM and nonconstitutional trisomy 21 and those with TAM and constitutional trisomy 21/DS (five-year overall survival: 76% ± 10% vs 53% ± 13%, P = 0.40; five-year event-free survival: 55% ± 13% vs 48% ± 12%, P = 0.90). The five-year cumulative incidence of progression to myeloid leukemia of DS was also similar between the groups (21% vs 24%, P = 0.80). CONCLUSIONS: Patients with TAM and nonconstitutional trisomy 21 exhibited similar biology and outcomes to those with TAM and constitutional trisomy 21/DS. The possibility of TAM should be considered even in phenotypically normal neonates with TAM symptoms, for appropriate management.
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Cromosomas Humanos Par 21/genética , Síndrome de Down , Factor de Transcripción GATA1/genética , Mutación , Mielopoyesis/genética , Supervivencia sin Enfermedad , Síndrome de Down/genética , Síndrome de Down/mortalidad , Síndrome de Down/patología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Tasa de SupervivenciaRESUMEN
A 3-year-old boy was clinically diagnosed with Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis. We identified EBV-infected CD8-positive T-lymphocytes by cytologic double staining of the peripheral blood for EBV-encoded small RNA and cell surface markers. The patient was subsequently administered immunosuppressive therapy with a reduced dose of etoposide because of previous organ damage. EBV clearance was confirmed by serial quantification of cell-fractionated EBV-DNA, whereas EBV-DNA persisted in the plasma for 18 weeks. Immunochemotherapy with low-dose etoposide combined with serial viral load monitoring is a potential therapeutic option for severe EBV-hemophagocytic lymphohistiocytosis cases with organ damage.
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Biomarcadores/análisis , Citodiagnóstico/métodos , Infecciones por Virus de Epstein-Barr/diagnóstico , Herpesvirus Humano 4/genética , Linfohistiocitosis Hemofagocítica/diagnóstico , ARN Pequeño no Traducido/genética , ARN Viral/genética , Linfocitos T CD8-positivos/virología , Preescolar , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Linfohistiocitosis Hemofagocítica/complicaciones , Linfohistiocitosis Hemofagocítica/virología , Masculino , Pronóstico , Coloración y Etiquetado , Carga ViralRESUMEN
The authors report two siblings with familial neuroblastoma with a germline R1275Q mutation of the tyrosine kinase domain of ALK. Whole exome sequencing and copy number variation assay were performed to investigate genetic alterations in the two cases. No common somatic mutations or gene polymorphisms related to the tumorigenesis of neuroblastoma were detected. A distinct pattern involving both segmental chromosomal alteration and MYCN amplification was detected. The diversity of biological behavior of familial neuroblastoma harboring a germline ALK mutation may depend on conventional prognostic factors, such as segmental chromosomal alterations and MYCN amplification, rather than additional acquired mutations.
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Quinasa de Linfoma Anaplásico/genética , Mutación de Línea Germinal , Neoplasias Primarias Múltiples/genética , Neuroblastoma/genética , Neoplasias de las Glándulas Suprarrenales/genética , Preescolar , Exoma , Femenino , Humanos , Lactante , Neoplasias Hepáticas/genética , Masculino , Neoplasias del Mediastino/genética , Linaje , Fenotipo , Mutación Puntual , Neoplasias de la Columna Vertebral/genéticaRESUMEN
Inherited bone-marrow-failure syndromes (IBMFSs) include heterogeneous genetic disorders characterized by bone-marrow failure, congenital anomalies, and an increased risk of malignancy. Many lines of evidence have suggested that p53 activation might be central to the pathogenesis of IBMFSs, including Diamond-Blackfan anemia (DBA) and dyskeratosis congenita (DC). However, the exact role of p53 activation in each clinical feature remains unknown. Here, we report unique de novo TP53 germline variants found in two individuals with an IBMFS accompanied by hypogammaglobulinemia, growth retardation, and microcephaly mimicking DBA and DC. TP53 is a tumor-suppressor gene most frequently mutated in human cancers, and occasional germline variants occur in Li-Fraumeni cancer-predisposition syndrome. Most of these mutations affect the core DNA-binding domain, leading to compromised transcriptional activities. In contrast, the variants found in the two individuals studied here caused the same truncation of the protein, resulting in the loss of 32 residues from the C-terminal domain (CTD). Unexpectedly, the p53 mutant had augmented transcriptional activities, an observation not previously described in humans. When we expressed this mutant in zebrafish and human-induced pluripotent stem cells, we observed impaired erythrocyte production. These findings together with close similarities to published knock-in mouse models of TP53 lacking the CTD demonstrate that the CTD-truncation mutations of TP53 cause IBMFS, providing important insights into the previously postulated connection between p53 and IBMFSs.
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Enfermedades de la Médula Ósea/genética , Médula Ósea/patología , Células Germinativas/patología , Mutación/genética , Proteína p53 Supresora de Tumor/genética , Adolescente , Adulto , Agammaglobulinemia/genética , Anemia de Diamond-Blackfan/genética , Animales , Preescolar , Eritrocitos/patología , Femenino , Trastornos del Crecimiento/genética , Humanos , Células Madre Pluripotentes Inducidas/patología , Lactante , Recién Nacido , Masculino , Ratones , Persona de Mediana Edad , Adulto Joven , Pez CebraAsunto(s)
Anemia de Diamond-Blackfan/genética , Exoma , Haploinsuficiencia , Mutación Puntual , ARN Ribosómico 18S/genética , Proteínas Ribosómicas/genética , Adulto , Empalme Alternativo , Anemia de Diamond-Blackfan/metabolismo , Anemia de Diamond-Blackfan/patología , Animales , Sistemas CRISPR-Cas , Proliferación Celular , Preescolar , Embrión no Mamífero , Exones , Femenino , Edición Génica , Expresión Génica , Humanos , Lactante , Células K562 , Linaje , ARN Ribosómico 18S/metabolismo , Proteínas Ribosómicas/deficiencia , Hermanos , Secuenciación del Exoma , Pez CebraRESUMEN
MDM2, an E3 ubiquitin ligase, is an important negative regulator of tumor suppressor p53. In turn the Mdm2 gene is a transcriptional target of p53, forming a negative feedback loop that is important in cell cycle control. It has recently become apparent that the ubiquitination of p53 by MDM2 can be inhibited when certain ribosomal proteins, including RPL5 and RPL11, bind to MDM2. This inhibition, and the resulting increase in p53 levels has been proposed to be responsible for the red cell aplasia seen in Diamond-Blackfan anemia (DBA) and in 5q- myelodysplastic syndrome (MDS). DBA and 5q- MDS are associated with inherited (DBA) or acquired (5q- MDS) haploinsufficiency of ribosomal proteins. A mutation in Mdm2 causing a C305F amino acid substitution blocks the binding of ribosomal proteins. Mice harboring this mutation (Mdm2C305F), retain a normal p53 response to DNA damage, but lack the p53 response to perturbations in ribosome biogenesis. While studying the interaction between RP haploinsufficiency and the Mdm2C305F mutation we noticed that Mdm2C305F homozygous mice had altered hematopoiesis. These mice developed a mild macrocytic anemia with reticulocytosis. In the bone marrow (BM), these mice showed a significant decrease in Ter119hi cells compared to wild type (WT) littermates, while no decrease in the number of mature erythroid cells (Ter119hiCD71low) was found in the spleen, which showed compensated bone marrow hematopoiesis. In methylcellulose cultures, BFU-E colonies from the mutant mice were slightly reduced in number and there was a significant reduction in CFU-E colony numbers in mutant mice compared with WT controls (p < 0.01). This erythropoietic defect was abrogated by concomitant p53 deficiency (Trp53ko/ko). Further investigation revealed that in Mdm2C305F animals, there was a decrease in Lin-Sca-1+c-Kit+ (LSK) cells, accompanied by significant decreases in multipotent progenitor (MPP) cells (p < 0.01). Competitive BM repopulation experiments showed that donor BM harboring the Mdm2C305F mutation possessed decreased repopulation capacity compared to WT BM, suggesting a functional stem cell deficit. These results suggest that there is a fine tuned balance in the interaction of ribosomal proteins with the MDM2/p53 axis which is important in normal hematopoiesis.
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Médula Ósea/metabolismo , Células Eritroides/metabolismo , Eritropoyesis , Mutación Missense , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Ribosómicas/metabolismo , Sustitución de Aminoácidos , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/metabolismo , Anemia de Diamond-Blackfan/patología , Animales , Médula Ósea/patología , Células Eritroides/patología , Haploinsuficiencia , Ratones , Ratones Noqueados , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/patología , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Ribosómicas/genética , Ribosomas/genética , Ribosomas/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
In Western countries, gene alterations involving the CRLF2-JAK signaling pathway are identified in approximately 50-60% of patients with Down syndrome-associated acute lymphoblastic leukemia (DS-ALL), and this pathway is considered a potential therapeutic target. The frequency of BTG1 deletions in DS-ALL is controversial. IKZF1 deletions, found in 20-30% of DS-ALL patients, are associated with a poor outcome and EBF1 deletions are very rare (â¼2%). We analyzed 38 patients to determine the frequencies and clinical implications of CRLF2-JAK pathway genetic alterations and recurrent gene deletions in Japanese DS-ALL patients. We confirmed a high incidence of P2RY8-CRLF2 (29%) and JAK2 mutations (16%), though the frequency of P2RY8-CRLF2 was slightly lower than that in Western countries (â¼50%). BTG1 deletions were common in our cohort (25%). IKZF1 deletions were detected in 25% of patients and associated with shorter overall survival (OS). EBF1 deletions were found at an unexpectedly high frequency (16%), and at a significantly higher level in P2RY8-CRLF2-positive patients than in P2RY8-CRLF2-negative patients (44% vs. 4%, P=0.015). Deletions of CDKN2A/B and PAX5 were common in P2RY8-CRLF2-negative patients (48 and 39%, respectively) but not in P2RY8-CRLF2-positive patients (11% each). Associations between these genetic alterations and clinical characteristics were not observed except for inferior OS in patients with IKZF1 deletions. These results suggest that differences exist between the genetic profiles of DS-ALL patients in Japan and in Western countries, and that P2RY8-CRLF2 and EBF1 deletions may cooperate in leukemogenesis in a subset of Japanese DS-ALL patients.