Infantile Myelofibrosis and Myeloproliferation with CDC42 Dysfunction

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

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)554-566
Number of pages13
JournalJournal of Clinical Immunology
Volume40
Issue number4
DOIs
StatePublished - May 1 2020
Externally publishedYes

Keywords

  • bone marrow microenvironment
  • Primary Myelofibrosis
  • Rho GTPases

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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