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

doi:10.1007/s10875-020-00778-7

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 journal › Article › peer-review

25 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 language	English (US)
Pages (from-to)	554-566
Number of pages	13
Journal	Journal of Clinical Immunology
Volume	40
Issue number	4
DOIs	https://doi.org/10.1007/s10875-020-00778-7
State	Published - May 1 2020
Externally published	Yes

Keywords

Primary Myelofibrosis
Rho GTPases
bone marrow microenvironment

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s10875-020-00778-7

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Verboon, J. M., Mahmut, D., Kim, A. R., Nakamura, M., Abdulhay, N. J., Nandakumar, S. K., Gupta, N., Akie, T. E., Geddis, A. E., Manes, B., Kapp, M. E., Hofmann, I., Gabriel, S. B., Klein, D. E., Williams, D. A., Frangoul, H. A., Parkhurst, S. M., Crane, G. M., Cantor, A. B., & Sankaran, V. G. (2020). Infantile Myelofibrosis and Myeloproliferation with CDC42 Dysfunction. Journal of Clinical Immunology, 40(4), 554-566. https://doi.org/10.1007/s10875-020-00778-7

Verboon, JM, Mahmut, D, Kim, AR, Nakamura, M, Abdulhay, NJ, Nandakumar, SK, Gupta, N, Akie, TE, Geddis, AE, Manes, B, Kapp, ME, Hofmann, I, Gabriel, SB, Klein, DE, Williams, DA, Frangoul, HA, Parkhurst, SM, Crane, GM, Cantor, AB & Sankaran, VG 2020, 'Infantile Myelofibrosis and Myeloproliferation with CDC42 Dysfunction', Journal of Clinical Immunology, vol. 40, no. 4, pp. 554-566. https://doi.org/10.1007/s10875-020-00778-7

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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.",

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AU - Nandakumar, Satish K.

AU - Gupta, Namrata

AU - Akie, Thomas E.

AU - Geddis, Amy E.

AU - Manes, Becky

AU - Kapp, Meghan E.

AU - Hofmann, Inga

AU - Gabriel, Stacey B.

AU - Klein, Daryl E.

AU - Williams, David A.

AU - Frangoul, Haydar A.

AU - Parkhurst, Susan M.

AU - Crane, Genevieve M.

AU - Cantor, Alan B.

AU - Sankaran, Vijay G.

PY - 2020/5/1

Y1 - 2020/5/1

N2 - 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.

AB - 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.

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Infantile Myelofibrosis and Myeloproliferation with CDC42 Dysfunction

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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