Published in:
Open Access
01-05-2020 | Primary Myelofibrosis | Original Article
Infantile Myelofibrosis and Myeloproliferation with CDC42
Dysfunction
Authors:
Jeffrey M. Verboon, Dilnar Mahmut, Ah Ram Kim, Mitsutoshi Nakamura, Nour J. Abdulhay, Satish K. Nandakumar, Namrata Gupta, Thomas E. Akie, Amy E. Geddis, Becky Manes, Meghan E. Kapp, Inga Hofmann, Stacey B. Gabriel, Daryl E. Klein, David A. Williams, Haydar A. Frangoul, Susan M. Parkhurst, Genevieve M. Crane, Alan B. Cantor, Vijay G. Sankaran
Published in:
Journal of Clinical Immunology
|
Issue 4/2020
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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.