Platelet transcriptome analysis in patients with germline RUNX1 mutations

Verónica Palma-Barqueros1, José María Bastida2, María José López Andreo3, Ana Zamora Cánovas1, Carlo Zaninetti4, Juan Francisco Ruiz-Pividal1, Natalia Bohdan1, José Padilla1, Raúl Teruel-Montoya1, Ana Marín-Quilez1,2, Nuria Revilla5, Ana Sánchez-Fuentes1, Agustín Rodriguez-Alen6, Rocío Benit2, Vicente Vicente1,  Teodoro Iturbe7, Andreas Greinacher4, María Luisa Lozano1,8, José Rivera1,8 | On behalf of Grupo Español de Alteraciones Plaquetarias Congénitas (GEAPC), Spanish Society of Thrombosis and Haemostasis (SETH)

  1. Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-U765, Murcia, Spain
  2. Department of Hematology, Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca (USAL), Salamanca, Spain
  3. Molecular Biology Section, University of Murcia, IMIB-CSVA, Murcia, Spain
  4. Institut für Transfusionsmedizin, Universitätsmedizin Greifswald, Greifswald, Germany
  5. Department of Hematology, Hospital Universitario Fundación Jiménez Díaz, Instituto Investigación Sanitaria FJD (IISFJD), Madrid, Spain
  6. Servicio de Hematología, Hospital Virgen de la Salud, Complejo Hospitalario de Toledo, Toledo, Spain
  7. Servicio de Hematología, Hospital Universitario Santa Lucía, Cartagena, Murcia, Spain
  8. Senior authors

J Thromb Haemost. 2023;▪:1–14; Published: February 01, 2023 DOI:· PIIS1538783623000727.pdf


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.

To extend the characterization of RUNX1 variants and evaluate their effects by transcriptome analysis

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.

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.

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.

Keywords: high-throughput sequencing, inherited thrombocytopenias, leukemia, myelodysplastic syndrome, platelet transcriptomics, RUNX1-familial platelet disorder

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