論文 - 詳細
| RRC ID | 65550 |
|---|---|
| 著者 | Antony-Debré I, Manchev VT, Balayn N, Bluteau D, Tomowiak C, Legrand C, Langlois T, Bawa O, Tosca L, Tachdjian G, Leheup B, Debili N, Plo I, Mills JA, French DL, Weiss MJ, Solary E, Favier R, Vainchenker W, Raslova H. |
| タイトル | Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia. |
| ジャーナル | Blood |
| Abstract |
To explore how RUNX1 mutations predispose to leukemia, we generated induced pluripotent stem cells (iPSCs) from 2 pedigrees with germline RUNX1 mutations. The first, carrying a missense R174Q mutation, which acts as a dominant-negative mutant, is associated with thrombocytopenia and leukemia, and the second, carrying a monoallelic gene deletion inducing a haploinsufficiency, presents only as thrombocytopenia. Hematopoietic differentiation of these iPSC clones demonstrated profound defects in erythropoiesis and megakaryopoiesis and deregulated expression of RUNX1 targets. iPSC clones from patients with the R174Q mutation specifically generated an increased amount of granulomonocytes, a phenotype reproduced by an 80% RUNX1 knockdown in the H9 human embryonic stem cell line, and a genomic instability. This phenotype, found only with a lower dosage of RUNX1, may account for development of leukemia in patients. Altogether, RUNX1 dosage could explain the differential phenotype according to RUNX1 mutations, with a haploinsufficiency leading to thrombocytopenia alone in a majority of cases whereas a more complete gene deletion predisposes to leukemia. |
| 巻・号 | 125(6) |
| ページ | 930-40 |
| 公開日 | 2015-2-5 |
| DOI | 10.1182/blood-2014-06-585513 |
| PII | S0006-4971(20)39476-3 |
| PMID | 25490895 |
| PMC | PMC4347283 |
| MeSH | Cell Line Cells, Cultured Core Binding Factor Alpha 2 Subunit / genetics* Core Binding Factor Alpha 2 Subunit / metabolism Gene Deletion Genetic Predisposition to Disease Genomic Instability Hematopoiesis* Humans Induced Pluripotent Stem Cells / cytology Induced Pluripotent Stem Cells / metabolism Induced Pluripotent Stem Cells / pathology Leukemia / genetics* Leukemia / metabolism Leukemia / pathology Molecular Sequence Data Mutation* Mutation, Missense Thrombocytopenia / genetics* Thrombocytopenia / metabolism Thrombocytopenia / pathology |
| IF | 17.794 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | F1000Research |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | OP9(RCB1124) |