A novel mutation in MECOM affects MPL regulation in vitro and results in thrombocytopenia and bone marrow failure

Author:

Ammeti Daniele1ORCID,Marzollo Antonio2,Gabelli Maria23ORCID,Zanchetta Melania Eva1,Tretti‐Parenzan Caterina23,Bottega Roberta1,Capaci Valeria1,Biffi Alessandra23,Savoia Anna4ORCID,Bresolin Silvia23ORCID,Faleschini Michela1ORCID

Affiliation:

1. Institute for Maternal and Child Health, IRCCS Burlo Garofolo Trieste Italy

2. Pediatric Hematology, Oncology and Stem Cell Transplant Division Padua University Hospital Padua Italy

3. Maternal and Child Health Department Padua University Padua Italy

4. Department of Engineering for Innovation Medicine University of Verona Verona Italy

Abstract

SummaryMECOM‐associated syndrome (MECOM‐AS) is a rare disease characterized by amegakaryocytic thrombocytopenia, progressive bone marrow failure, pancytopenia and radioulnar synostosis with high penetrance. The clinical phenotype may also include finger malformations, cardiac and renal alterations, hearing loss, B‐cell deficiency and predisposition to infections. The syndrome, usually diagnosed in the neonatal period because of severe thrombocytopenia, is caused by mutations in the MECOM gene, encoding for the transcription factor EVI1. The mechanism linking the alteration of EVI1 function and thrombocytopenia is poorly understood. In a paediatric patient affected by severe thrombocytopenia, we identified a novel variant of the MECOM gene (p.P634L), whose effect was tested on pAP‐1 enhancer element and promoters of targeted genes showing that the mutation impairs the repressive activity of the transcription factor. Moreover, we demonstrated that EVI1 controls the transcriptional regulation of MPL, a gene whose mutations are responsible for congenital amegakaryocytic thrombocytopenia (CAMT), potentially explaining the partial overlap between MECOM‐AS and CAMT.

Funder

Ministero della Salute

Publisher

Wiley

Subject

Hematology

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