Infantile Myelofibrosis and Myeloproliferation with CDC42Dysfunction
Abstract Studies of genetic blood disorders have advanced our understanding ofthe intrinsic regulation of hematopoiesis. However, such genetic studies have onlyyielded limited insights into how interactions between hematopoietic cells and theirmicroenvironment are regulated. Here, we describe two affected siblings withinfantile myelofibrosis and myeloproliferation that share a common de novo mutationin the Rho GTPase CDC42 (Chr1:22417990:C>T, p.R186C) due to paternal germlinemosaicism. Functional studies using human cells and flies demonstrate that thisCDC42 mutant has altered activity and thereby disrupts interactions betweenhematopoietic progenitors and key tissue microenvironmental factors. These findingssuggest that further investigation of this and other related disorders may provideinsights into how hematopoietic cell-microenvironment interactions play a role inhuman health and can be disrupted in disease. In addition, we suggest thatderegulation of CDC42 may underlie more common blood disorders, such as primarymyelofibrosis..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:40 |
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| Enthalten in: |
Journal of clinical immunology - 40(2020), 4 vom: 17. Apr., Seite 554-566 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Verboon, Jeffrey M. [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| BKL: | |
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| Themen: |
Bone marrow microenvironment |
| doi: |
10.1007/s10875-020-00778-7 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Abstract Studies of genetic blood disorders have advanced our understanding ofthe intrinsic regulation of hematopoiesis. However, such genetic studies have onlyyielded limited insights into how interactions between hematopoietic cells and theirmicroenvironment are regulated. Here, we describe two affected siblings withinfantile myelofibrosis and myeloproliferation that share a common de novo mutationin the Rho GTPase CDC42 (Chr1:22417990:C>T, p.R186C) due to paternal germlinemosaicism. Functional studies using human cells and flies demonstrate that thisCDC42 mutant has altered activity and thereby disrupts interactions betweenhematopoietic progenitors and key tissue microenvironmental factors. These findingssuggest that further investigation of this and other related disorders may provideinsights into how hematopoietic cell-microenvironment interactions play a role inhuman health and can be disrupted in disease. In addition, we suggest thatderegulation of CDC42 may underlie more common blood disorders, such as primarymyelofibrosis. | ||
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