Infantile Myelofibrosis and Myeloproliferation with CDC42 Dysfunction
- PDF / 1,282,063 Bytes
- 13 Pages / 595.276 x 790.866 pts Page_size
- 90 Downloads / 213 Views
ORIGINAL ARTICLE
Infantile Myelofibrosis and Myeloproliferation with CDC42 Dysfunction Jeffrey M. Verboon 1,2 & Dilnar Mahmut 1,2 & Ah Ram Kim 1,2 & Mitsutoshi Nakamura 3 & Nour J. Abdulhay 1,2 & Satish K. Nandakumar 1,2 & Namrata Gupta 2 & Thomas E. Akie 1 & Amy E. Geddis 4 & Becky Manes 5 & Meghan E. Kapp 6 & Inga Hofmann 1,7 & Stacey B. Gabriel 2 & Daryl E. Klein 8 & David A. Williams 1 & Haydar A. Frangoul 9 & Susan M. Parkhurst 3 & Genevieve M. Crane 10 & Alan B. Cantor 1 & Vijay G. Sankaran 1,2 Received: 2 January 2020 / Accepted: 30 March 2020 # The Author(s) 2020
Abstract Studies of genetic blood disorders have advanced our understanding of the intrinsic regulation of hematopoiesis. However, such genetic studies have only yielded limited insights into how interactions between hematopoietic cells and their microenvironment are regulated. Here, we describe two affected siblings with infantile myelofibrosis and myeloproliferation that share a common de novo mutation in the Rho GTPase CDC42 (Chr1:22417990:C>T, p.R186C) due to paternal germline mosaicism. Functional studies using human cells and flies demonstrate that this CDC42 mutant has altered activity and thereby disrupts interactions between hematopoietic progenitors and key tissue microenvironmental factors. These findings suggest that further investigation of this and other related disorders may provide insights into how hematopoietic cell-microenvironment interactions play a role in human health and can be disrupted in disease. In addition, we suggest that deregulation of CDC42 may underlie more common blood disorders, such as primary myelofibrosis. Keywords Primary Myelofibrosis . Rho GTPases . bone marrow microenvironment
Introduction Recent studies have provided considerable insights into how interactions between hematopoietic stem/progenitor cells and their microenvironment are regulated [5, 10, 34, 44]. Despite the substantial progress in this field, it remains unclear whether perturbation of such interactions can lead to human disease.
Rare experiments of nature provide a potentially effective way to gain insights into how these interactions function normally in health and can be perturbed in disease states. For instance, a recent study demonstrated that chromothriptic disruption of a gain-of-function mutation in CXCR4 in hematopoietic stem cells (HSCs) was curative in a patient with warts, hypogammaglobulinemia, immunodeficiency, and
Jeffrey M. Verboon and Dilnar Mahmut contributed equally to this work. * Alan B. Cantor [email protected]
5
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA
* Vijay G. Sankaran [email protected]
6
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
7
Division of Hematology, Oncology, and Bone Marrow Transplantation, Department of Pediatrics, University of Wisconsin, Madison, WI, USA
8
Department of Pharmacology, Yale Cancer Biology Institute, Yale University School of Medicine, Wes
Data Loading...