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.
Highlights
Recent studies have provided considerable insights into how interactions between hematopoietic stem/progenitor cells and their microenvironment are regulated [5, 10, 34, 44]
Our studies extend the phenotypic spectrum of disorders resulting from mutations of Rho GTPases and implicate the CDC42 R186C mutation in altering interactions of hematopoietic cells with the microenvironment
At 2 months of age, he underwent bone marrow transplantation (BMT) with his 4-year-old female HLAmatched sibling serving as the donor
Summary
Recent studies have provided considerable insights into how interactions between hematopoietic stem/progenitor cells and their microenvironment are regulated [5, 10, 34, 44]. Mouse models have demonstrated that perturbations of the HSC niche can impact the function and differentiation of hematopoietic cells, as exemplified by mutations in the bone marrow microenvironment causing myeloproliferative disorders [34, 47, 48]. We demonstrate dysfunctional activity of this mutant form of CDC42 Introduction of this mutation into primary human hematopoietic stem/progenitor cells disrupts the ability of the cells to migrate towards the key hematopoietic chemokine, CXCL12/SDF-1 [10]. Our studies extend the phenotypic spectrum of disorders resulting from mutations of Rho GTPases and implicate the CDC42 R186C mutation in altering interactions of hematopoietic cells with the microenvironment. Studies of acquired primary myelofibrosis suggest that disruption of CDC42 may occur in hematopoietic progenitor cells in this disease, connecting the observations made in these rare cases to the pathogenesis of other, more common, acquired malignant hematopoietic disorders
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