Bone marrow failure unresponsive to bone marrow transplant is caused by mutations in thrombopoietin

• Verfasst von: Seo, Aaron [VerfasserIn]
• Verfasst von: Stockklausner, Clemens [VerfasserIn]
• Verfasst von: Kulozik, Andreas [VerfasserIn]
• Titel: Bone marrow failure unresponsive to bone marrow transplant is caused by mutations in thrombopoietin
• Verf.angabe: Aaron Seo, Miri Ben-Harosh, Mehtap Sirin, Jerry Stein, Orly Dgany, Joseph Kaplelushnik, Manfred Hoenig, Ulrich Pannicke, Myriam Lorenz, Klaus Schwarz, Clemens Stockklausner, Tom Walsh, Suleyman Gulsuner, Ming K. Lee, Anoop Sendamarai, Marilyn Sanchez-Bonilla, Mary-Claire King, Holger Cario, Andreas E. Kulozik, Klaus-Michael Debatin, Ansgar Schulz, Hannah Tamary, and Akiko Shimamura
• Umfang: 6 S.
• Fussnoten: Gesehen am 11.07.2018
• Titel Quelle: Enthalten in: Blood
• Jahr Quelle: 2017
• Band/Heft Quelle: 130(2017), 7, S. 875-880
• ISSN Quelle: 1528-0020
• DOI: doi:10.1182/blood-2017-02-768036
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1577495381

Abstract

We report 5 individuals in 3 unrelated families with severe thrombocytopenia progressing to trilineage bone marrow failure (BMF). Four of the children received hematopoietic stem cell transplants and all showed poor graft function with persistent severe cytopenias even after repeated transplants with different donors. Exome and targeted sequencing identified mutations in the gene encoding thrombopoietin (THPO): THPO R99W, homozygous in affected children in 2 families, and THPO R157X, homozygous in the affected child in the third family. Both mutations result in a lack of THPO in the patients’ serum. For the 2 surviving patients, improvement in trilineage hematopoiesis was achieved following treatment with a THPO receptor agonist. These studies demonstrate that biallelic loss-of-function mutations in THPO cause BMF, which is unresponsive to transplant due to a hematopoietic cell-extrinsic mechanism. These studies provide further support for the critical role of the MPL-THPO pathway in hematopoiesis and highlight the importance of accurate genetic diagnosis to inform treatment decisions for BMF.