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Blood. 2017 Aug 17;130(7):875-880. doi: 10.1182/blood-2017-02-768036. Epub 2017 May 30.

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

Author information

1
Department of Genome Sciences and.
2
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA.
3
Department of Pediatric Hematology/Oncology, Soroka Medical Center, Faculty of Medicine, Ben-Gurion University, Beer Sheva, Israel.
4
Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.
5
Bone Marrow Transplant Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
6
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
7
Pediatric Hematology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel.
8
Institute for Transfusion Medicine, University Ulm, Ulm, Germany.
9
Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Württemberg-Hessen, Ulm, Germany.
10
Department of Pediatric Hematology and Oncology, Heidelberg University, Heidelberg, Germany.
11
Department of Pathology, Boston Children's Hospital, Boston, MA.
12
Department of Pediatric Hematology/Oncology, Boston Children's Hospital/Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA; and.
13
Hematology Unit, Schneider Children's Medical Center of Israel, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

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.

PMID:
28559357
PMCID:
PMC5561901
DOI:
10.1182/blood-2017-02-768036
[Indexed for MEDLINE]
Free PMC Article

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