Infantile Myelofibrosis and Myeloproliferation with CDC42 Dysfunction.

Autor: Verboon JM; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Mahmut D; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Kim AR; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Nakamura M; Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Abdulhay NJ; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Nandakumar SK; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Gupta N; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Akie TE; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Geddis AE; Cancer and Blood Disorders Clinic, Seattle Children's Hospital, Seattle, WA, USA., Manes B; Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA., Kapp ME; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA., Hofmann I; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.; Division of Hematology, Oncology, and Bone Marrow Transplantation, Department of Pediatrics, University of Wisconsin, Madison, WI, USA., Gabriel SB; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Klein DE; Department of Pharmacology, Yale Cancer Biology Institute, Yale University School of Medicine, West Haven, CT, USA., Williams DA; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Frangoul HA; The Children's Hospital at TriStar Centennial, Sarah Cannon Research Institute, Nashville, TN, USA., Parkhurst SM; Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Crane GM; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA., Cantor AB; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. alan.cantor@childrens.harvard.edu., Sankaran VG; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. sankaran@broadinstitute.org.; Broad Institute of MIT and Harvard, Cambridge, MA, USA. sankaran@broadinstitute.org.
Jazyk: angličtina
Zdroj: Journal of clinical immunology [J Clin Immunol] 2020 May; Vol. 40 (4), pp. 554-566. Date of Electronic Publication: 2020 Apr 17.
DOI: 10.1007/s10875-020-00778-7
Abstrakt: 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.
Databáze: MEDLINE