RESUMEN
Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially life-threatening hematologic disease, presenting a myriad of diagnostic and management challenges in children. Here, we provide a review of this disorder and discuss 2 exemplary cases of TTP occurring in adolescents, emphasizing the need for consideration of late-onset congenital TTP (cTTP). We demonstrate the importance of early confirmation of ADAMTS13 enzyme deficiency and the presence or absence of ADAMTS13 inhibitor in order to rapidly initiate the appropriate life-saving therapies. Ultimately, molecular testing is paramount to distinguishing between congenital and acquired immune-mediated TTP.
Asunto(s)
Púrpura Trombocitopénica Trombótica , Adolescente , Niño , Humanos , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/genética , Púrpura Trombocitopénica Trombótica/terapiaRESUMEN
The Hedgehog (Hh) signaling pathway regulates normal development and cell proliferation in metazoan organisms, but its aberrant activation can promote tumorigenesis. Hh-induced tumors arise from various tissues and they may be indolent or aggressive, as is the case with skin basal cell carcinoma (BCC) or cerebellar medulloblastoma, respectively. Little is known about common cell-intrinsic factors that control the development of such diverse Hh-dependent tumors. Transcription factor Zfx is required for the self-renewal of hematopoietic and embryonic stem cells, as well as for the propagation of acute myeloid and T-lymphoblastic leukemias. We report here that Zfx facilitates the development of experimental BCC and medulloblastoma in mice initiated by deletion of the Hh inhibitory receptor Ptch1. Simultaneous deletion of Zfx along with Ptch1 prevented BCC formation and delayed medulloblastoma development. In contrast, Zfx was dispensable for tumorigenesis in a mouse model of glioblastoma. We used genome-wide expression and chromatin-binding analysis in a human medulloblastoma cell line to characterize direct, evolutionarily conserved targets of Zfx, identifying Dis3L and Ube2j1 as two targets required for the growth of the human medulloblastoma cells. Our results establish Zfx as a common cell-intrinsic regulator of diverse Hh-induced tumors, with implications for the definition of new therapeutic targets in these malignancies.
Asunto(s)
Carcinogénesis/genética , Proteínas Hedgehog/metabolismo , Factores de Transcripción de Tipo Kruppel/fisiología , Animales , Carcinoma Basocelular/genética , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patología , Línea Celular Tumoral , Proliferación Celular , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/metabolismo , Técnicas de Inactivación de Genes , Humanos , Masculino , Meduloblastoma/genética , Meduloblastoma/metabolismo , Ratones Noqueados , Receptores Patched , Receptor Patched-1 , Receptores de Superficie Celular/genética , Ribonucleasas/metabolismo , Transducción de Señal , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Enzimas Ubiquitina-Conjugadoras/metabolismoRESUMEN
Tumor-propagating cells in acute leukemia maintain a stem/progenitor-like immature phenotype and proliferative capacity. Acute myeloid leukemia (AML) and acute T-lymphoblastic leukemia (T-ALL) originate from different lineages through distinct oncogenic events such as MLL fusions and Notch signaling, respectively. We found that Zfx, a transcription factor that controls hematopoietic stem cell self-renewal, controls the initiation and maintenance of AML caused by MLL-AF9 fusion and of T-ALL caused by Notch1 activation. In both leukemia types, Zfx prevents differentiation and activates gene sets characteristic of immature cells of the respective lineages. In addition, endogenous Zfx contributes to gene induction and transformation by Myc overexpression in myeloid progenitors. Key Zfx target genes include the mitochondrial enzymes Ptpmt1 and Idh2, whose overexpression partially rescues the propagation of Zfx-deficient AML. These results show that distinct leukemia types maintain their undifferentiated phenotype and self-renewal by exploiting a common stem-cell-related genetic regulator.
Asunto(s)
Diferenciación Celular , Factores de Transcripción de Tipo Kruppel/metabolismo , Leucemia Mieloide Aguda/patología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Animales , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/patología , Células Clonales , Regulación Leucémica de la Expresión Génica , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Leucemia Mieloide Aguda/genética , Ratones , Mitocondrias/enzimología , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Fenotipo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptores Notch/metabolismoAsunto(s)
Antígenos Virales/genética , Proteínas de la Cápside/genética , Mutación Missense , Infecciones por Rotavirus/virología , Vacunas contra Rotavirus/efectos adversos , Esparcimiento de Virus , Antígenos Virales/inmunología , Proteínas de la Cápside/inmunología , Diarrea/virología , Heces/virología , Femenino , Humanos , Lactante , Proteínas Mutantes/genética , Proteínas Mutantes/inmunología , Vacunas contra Rotavirus/administración & dosificación , Inmunodeficiencia Combinada Grave/complicaciones , Inmunodeficiencia Combinada Grave/diagnósticoRESUMEN
Sickle cell disease (SCD) is a classic example of a disorder with recessive Mendelian inheritance, in which each parent contributes one mutant allele to an affected offspring. However, there are exceptions to that rule. We describe here the first reported case of conversion of inherited sickle cell trait to SCD by uniparental disomy (UPD) resulting in mosaicism for SS and AS erythrocytes. A 14-year-old boy presented with splenomegaly and hemolysis. Although his father has sickle cell trait, his mother has no abnormal hemoglobin (Hb). DNA sequencing, performed to rule out Hb S/ß-thalassemia, detected homozygous Hb SS. Further studies revealed mosaic UPD of the ß-globin locus, more SS erythroid progenitors than AS, but a reverse ratio of erythrocytes resulting from the survival advantage of AS erythrocytes. This report exemplifies non-Mendelian genetics wherein a patient who inherited sickle cell trait has mild SCD resulting from postzygotic mitotic recombination leading to UPD.