Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment

Lei Dong, Wen Mei Yu, Hong Zheng, Mignon L. Loh, Silvia T. Bunting, Melinda Pauly, Gang Huang, Muxiang Zhou, Hal Broxmeyer, David T. Scadden, Cheng Kui Qu

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Germline activating mutations of the protein tyrosine phosphatase SHP2 (encoded by PTPN11), a positive regulator of the RAS signalling pathway, are found in 50% of patients with Noonan syndrome. These patients have an increased risk of developing leukaemia, especially juvenile myelomonocytic leukaemia (JMML), a childhood myeloproliferative neoplasm (MPN). Previous studies have demonstrated that mutations in Ptpn11 induce a JMML-like MPN through cell-autonomous mechanisms that are dependent on Shp2 catalytic activity. However, the effect of these mutations in the bone marrow microenvironment remains unclear. Here we report that Ptpn11 activating mutations in the mouse bone marrow microenvironment promote the development and progression of MPN through profound detrimental effects on haematopoietic stem cells (HSCs). Ptpn11 mutations in mesenchymal stem/progenitor cells and osteoprogenitors, but not in differentiated osteoblasts or endothelial cells, cause excessive production of the CC chemokine CCL3 (also known as MIP-1α), which recruits monocytes to the area in which HSCs also reside. Consequently, HSCs are hyperactivated by interleukin-1β and possibly other proinflammatory cytokines produced by monocytes, leading to exacerbated MPN and to donor-cell-derived MPN following stem cell transplantation. Remarkably, administration of CCL3 receptor antagonists effectively reverses MPN development induced by the Ptpn11-mutated bone marrow microenvironment. This study reveals the critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukaemogenesis and identifies CCL3 as a potential therapeutic target for controlling leukaemic progression in Noonan syndrome and for improving stem cell transplantation therapy in Noonan-syndrome-associated leukaemias.

Original languageEnglish (US)
Pages (from-to)304-308
Number of pages5
JournalNature
Volume539
Issue number7628
DOIs
StatePublished - Nov 10 2016

Fingerprint

Stem Cell Niche
Noonan Syndrome
Mutation
Juvenile Myelomonocytic Leukemia
Hematopoietic Stem Cells
Bone Marrow
Neoplasms
Stem Cell Transplantation
Mesenchymal Stromal Cells
Monocytes
Leukemia
Chemokine CCL3
CC Chemokines
Protein Tyrosine Phosphatases
Germ-Line Mutation
Cell- and Tissue-Based Therapy
Osteoblasts
Interleukin-1
Endothelial Cells
Tissue Donors

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Dong, L., Yu, W. M., Zheng, H., Loh, M. L., Bunting, S. T., Pauly, M., ... Qu, C. K. (2016). Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment. Nature, 539(7628), 304-308. https://doi.org/10.1038/nature20131

Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment. / Dong, Lei; Yu, Wen Mei; Zheng, Hong; Loh, Mignon L.; Bunting, Silvia T.; Pauly, Melinda; Huang, Gang; Zhou, Muxiang; Broxmeyer, Hal; Scadden, David T.; Qu, Cheng Kui.

In: Nature, Vol. 539, No. 7628, 10.11.2016, p. 304-308.

Research output: Contribution to journalArticle

Dong, L, Yu, WM, Zheng, H, Loh, ML, Bunting, ST, Pauly, M, Huang, G, Zhou, M, Broxmeyer, H, Scadden, DT & Qu, CK 2016, 'Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment', Nature, vol. 539, no. 7628, pp. 304-308. https://doi.org/10.1038/nature20131
Dong L, Yu WM, Zheng H, Loh ML, Bunting ST, Pauly M et al. Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment. Nature. 2016 Nov 10;539(7628):304-308. https://doi.org/10.1038/nature20131
Dong, Lei ; Yu, Wen Mei ; Zheng, Hong ; Loh, Mignon L. ; Bunting, Silvia T. ; Pauly, Melinda ; Huang, Gang ; Zhou, Muxiang ; Broxmeyer, Hal ; Scadden, David T. ; Qu, Cheng Kui. / Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment. In: Nature. 2016 ; Vol. 539, No. 7628. pp. 304-308.
@article{28ca8e9212534b17aef7158e5a3fae09,
title = "Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment",
abstract = "Germline activating mutations of the protein tyrosine phosphatase SHP2 (encoded by PTPN11), a positive regulator of the RAS signalling pathway, are found in 50{\%} of patients with Noonan syndrome. These patients have an increased risk of developing leukaemia, especially juvenile myelomonocytic leukaemia (JMML), a childhood myeloproliferative neoplasm (MPN). Previous studies have demonstrated that mutations in Ptpn11 induce a JMML-like MPN through cell-autonomous mechanisms that are dependent on Shp2 catalytic activity. However, the effect of these mutations in the bone marrow microenvironment remains unclear. Here we report that Ptpn11 activating mutations in the mouse bone marrow microenvironment promote the development and progression of MPN through profound detrimental effects on haematopoietic stem cells (HSCs). Ptpn11 mutations in mesenchymal stem/progenitor cells and osteoprogenitors, but not in differentiated osteoblasts or endothelial cells, cause excessive production of the CC chemokine CCL3 (also known as MIP-1α), which recruits monocytes to the area in which HSCs also reside. Consequently, HSCs are hyperactivated by interleukin-1β and possibly other proinflammatory cytokines produced by monocytes, leading to exacerbated MPN and to donor-cell-derived MPN following stem cell transplantation. Remarkably, administration of CCL3 receptor antagonists effectively reverses MPN development induced by the Ptpn11-mutated bone marrow microenvironment. This study reveals the critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukaemogenesis and identifies CCL3 as a potential therapeutic target for controlling leukaemic progression in Noonan syndrome and for improving stem cell transplantation therapy in Noonan-syndrome-associated leukaemias.",
author = "Lei Dong and Yu, {Wen Mei} and Hong Zheng and Loh, {Mignon L.} and Bunting, {Silvia T.} and Melinda Pauly and Gang Huang and Muxiang Zhou and Hal Broxmeyer and Scadden, {David T.} and Qu, {Cheng Kui}",
year = "2016",
month = "11",
day = "10",
doi = "10.1038/nature20131",
language = "English (US)",
volume = "539",
pages = "304--308",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7628",

}

TY - JOUR

T1 - Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment

AU - Dong, Lei

AU - Yu, Wen Mei

AU - Zheng, Hong

AU - Loh, Mignon L.

AU - Bunting, Silvia T.

AU - Pauly, Melinda

AU - Huang, Gang

AU - Zhou, Muxiang

AU - Broxmeyer, Hal

AU - Scadden, David T.

AU - Qu, Cheng Kui

PY - 2016/11/10

Y1 - 2016/11/10

N2 - Germline activating mutations of the protein tyrosine phosphatase SHP2 (encoded by PTPN11), a positive regulator of the RAS signalling pathway, are found in 50% of patients with Noonan syndrome. These patients have an increased risk of developing leukaemia, especially juvenile myelomonocytic leukaemia (JMML), a childhood myeloproliferative neoplasm (MPN). Previous studies have demonstrated that mutations in Ptpn11 induce a JMML-like MPN through cell-autonomous mechanisms that are dependent on Shp2 catalytic activity. However, the effect of these mutations in the bone marrow microenvironment remains unclear. Here we report that Ptpn11 activating mutations in the mouse bone marrow microenvironment promote the development and progression of MPN through profound detrimental effects on haematopoietic stem cells (HSCs). Ptpn11 mutations in mesenchymal stem/progenitor cells and osteoprogenitors, but not in differentiated osteoblasts or endothelial cells, cause excessive production of the CC chemokine CCL3 (also known as MIP-1α), which recruits monocytes to the area in which HSCs also reside. Consequently, HSCs are hyperactivated by interleukin-1β and possibly other proinflammatory cytokines produced by monocytes, leading to exacerbated MPN and to donor-cell-derived MPN following stem cell transplantation. Remarkably, administration of CCL3 receptor antagonists effectively reverses MPN development induced by the Ptpn11-mutated bone marrow microenvironment. This study reveals the critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukaemogenesis and identifies CCL3 as a potential therapeutic target for controlling leukaemic progression in Noonan syndrome and for improving stem cell transplantation therapy in Noonan-syndrome-associated leukaemias.

AB - Germline activating mutations of the protein tyrosine phosphatase SHP2 (encoded by PTPN11), a positive regulator of the RAS signalling pathway, are found in 50% of patients with Noonan syndrome. These patients have an increased risk of developing leukaemia, especially juvenile myelomonocytic leukaemia (JMML), a childhood myeloproliferative neoplasm (MPN). Previous studies have demonstrated that mutations in Ptpn11 induce a JMML-like MPN through cell-autonomous mechanisms that are dependent on Shp2 catalytic activity. However, the effect of these mutations in the bone marrow microenvironment remains unclear. Here we report that Ptpn11 activating mutations in the mouse bone marrow microenvironment promote the development and progression of MPN through profound detrimental effects on haematopoietic stem cells (HSCs). Ptpn11 mutations in mesenchymal stem/progenitor cells and osteoprogenitors, but not in differentiated osteoblasts or endothelial cells, cause excessive production of the CC chemokine CCL3 (also known as MIP-1α), which recruits monocytes to the area in which HSCs also reside. Consequently, HSCs are hyperactivated by interleukin-1β and possibly other proinflammatory cytokines produced by monocytes, leading to exacerbated MPN and to donor-cell-derived MPN following stem cell transplantation. Remarkably, administration of CCL3 receptor antagonists effectively reverses MPN development induced by the Ptpn11-mutated bone marrow microenvironment. This study reveals the critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukaemogenesis and identifies CCL3 as a potential therapeutic target for controlling leukaemic progression in Noonan syndrome and for improving stem cell transplantation therapy in Noonan-syndrome-associated leukaemias.

UR - http://www.scopus.com/inward/record.url?scp=85016130633&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016130633&partnerID=8YFLogxK

U2 - 10.1038/nature20131

DO - 10.1038/nature20131

M3 - Article

C2 - 27783593

AN - SCOPUS:85016130633

VL - 539

SP - 304

EP - 308

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7628

ER -