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.

中文翻译：

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伴有 CDC42 功能障碍的婴儿骨髓纤维化和骨髓增生。

对遗传性血液疾病的研究增进了我们对造血功能的内在调节的理解。然而，此类遗传研究仅对造血细胞与其微环境之间的相互作用如何调节产生了有限的见解。在这里，我们描述了两个患有婴儿骨髓纤维化和骨髓增生的受影响兄弟姐妹，由于父系生殖系嵌合，它们在 Rho GTPase CDC42 (Chr1:22417990:C>T, p.R186C) 中有一个共同的从头突变。使用人类细胞和果蝇的功能研究表明，这种 CDC42 突变体的活性发生了改变，从而破坏了造血祖细胞与关键组织微环境因素之间的相互作用。这些发现表明，对这种疾病和其他相关疾病的进一步研究可能会深入了解造血细胞 - 微环境相互作用如何在人类健康中发挥作用，并可能在疾病中被破坏。此外，我们认为 CDC42 的失调可能是更常见的血液疾病（如原发性骨髓纤维化）的基础。