RESUMEN
BACKGROUND: Germline mutations in RUNX1 can cause a familial platelet disorder that may lead to acute myeloid leukemia, an autosomal dominant disorder characterized by moderate thrombocytopenia, platelet dysfunction, and a high risk of developing acute myeloid leukemia or myelodysplastic syndrome. Discerning the pathogenicity of novel RUNX1 variants is critical for patient management. OBJECTIVES: To extend the characterization of RUNX1 variants and evaluate their effects by transcriptome analysis. METHODS: Three unrelated patients with long-standing thrombocytopenia carrying heterozygous RUNX1 variants were included: P1, who is a subject with recent development of myelodysplastic syndrome, with c.802 C>T[p.Gln268∗] de novo; P2 with c.586A>G[p.Thr196Ala], a variant that segregates with thrombocytopenia and myeloid neoplasia in the family; and P3 with c.476A>G[p.Asn159Ser], which did not segregate with thrombocytopenia or neoplasia. Baseline platelet evaluations were performed. Ultrapure platelets were prepared for platelet transcriptome analysis. RESULTS: In P1 and P2, but not in P3, transcriptome analysis confirmed aberrant expression of genes recognized as RUNX1 targets. Data allowed grouping patients by distinct gene expression profiles, which were partitioned with clinical parameters. Functional studies and platelet mRNA expression identified alterations in the actin cytoskeleton, downregulation of GFI1B, defective GPVI downstream signaling, and reduction of alpha granule proteins, such as thrombospondin-1, as features likely implicated in thrombocytopenia and platelet dysfunction. CONCLUSION: Platelet phenotype, familial segregation, and platelet transcriptomics support the pathogenicity of RUNX1 variants p.Gln268∗ and p.Thr196Ala, but not p.Asn159Ser. This study is an additional proof of concept that platelet RNA analysis could be a tool to help classify pathogenic RUNX1 variants and identify novel RUNX1 targets.
Asunto(s)
Trastornos de las Plaquetas Sanguíneas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Trombocitopenia , Humanos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Mutación de Línea Germinal , Trastornos de las Plaquetas Sanguíneas/complicaciones , Trombocitopenia/genética , Trombocitopenia/complicaciones , Leucemia Mieloide Aguda/genética , Perfilación de la Expresión Génica , Células Germinativas/metabolismo , MutaciónRESUMEN
The dismal outcome of pleuropericardial extramedullary multiple myeloma (EMM) reflects both the selection of resistant disease and absence of useful drugs. Carfilzomib and dexamethasone should be explored in advanced EMM patients, even for bortezomib-resistant patients, as may provide much longer overall survival than previously reported treatments.
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No disponible
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Humanos , Masculino , Anciano de 80 o más Años , Trombocitopenia/inducido químicamente , Enoxaparina/efectos adversos , Trombosis/complicaciones , Fracturas de Cadera/complicacionesRESUMEN
No disponible
Asunto(s)
Humanos , Teorema de Bayes , Biomarcadores , Inhibidores de Agregación Plaquetaria , Aspirina , Proteína C-Reactiva , Enfermedad Coronaria , FibrinógenoRESUMEN
No disponible
