Non–lineage/stage-restricted effects of a gain-of-function mutation in tyrosine phosphatase <i>Ptpn11</i> (Shp2) on malignant transformation of hematopoietic cells

Xu, Dan; Liu, Xia; Yu, Wen Mei; Meyerson, Howard; Guo, Caiying; Gerson, Stanton L.; Qu, Cheng Kui

doi:10.1084/jem.20110450

Cited by 99 publications

(130 citation statements)

References 64 publications

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“…1B). Consistent with these results, conditional knock-in mice bearing another Ptpn11 GOF mutation (E76K) (18), which is stronger than the D61G mutation in activating the catalytic activity of Shp2 (9,20), showed much accelerated evolution into acute leukemias in response to 6 Gy irradiation (Fig. S1B), suggesting that the effects of Shp2 mutants on sensitizing DNA damage-induced malignancies correlate with their enhanced catalytic activities.…”

Section: Ptpn11 D61g Mutation Induces Chromosomal Instability and Incsupporting

confidence: 70%

“…In addition, disease-associated Ptpn11 mutations enhance the binding of mutant Shp2 to signaling partners (14)(15)(16). Recent studies have demonstrated that these gain-of-function (GOF) mutations of Ptpn11 are sufficient to drive the development of Noonan syndrome and leukemias in mice (15,17,18). Nevertheless, as the biochemical basis for the role that Shp2 plays in cell signaling is not well understood, the mechanisms of the tumorigenesis induced by Ptpn11 GOF mutations remain poorly defined.…”

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confidence: 99%

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Gain-of-function mutations of Ptpn11 (Shp2) cause aberrant mitosis and increase susceptibility to DNA damage-induced malignancies

Liu

Zheng

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Gain-of-function (GOF) mutations of protein tyrosine phosphatase nonreceptor type 11 Ptpn11 (Shp2), a protein tyrosine phosphatase implicated in multiple cell signaling pathways, are associated with childhood leukemias and solid tumors. The underlying mechanisms are not fully understood. Here, we report that Ptpn11 GOF mutations disturb mitosis and cytokinesis, causing chromosomal instability and greatly increased susceptibility to DNA damage-induced malignancies. We find that Shp2 is distributed to the kinetochore, centrosome, spindle midzone, and midbody, all of which are known to play critical roles in chromosome segregation and cytokinesis. Mouse embryonic fibroblasts with Ptpn11 GOF mutations show a compromised mitotic checkpoint. Centrosome amplification and aberrant mitosis with misaligned or lagging chromosomes are significantly increased in Ptpn11-mutated mouse and patient cells. Abnormal cytokinesis is also markedly increased in these cells. Further mechanistic analyses reveal that GOF mutant Shp2 hyperactivates the Polo-like kinase 1 (Plk1) kinase by enhancing c-Src kinase-mediated tyrosine phosphorylation of Plk1. This study provides novel insights into the tumorigenesis associated with Ptpn11 GOF mutations and cautions that DNA-damaging treatments in Noonan syndrome patients with germ-line Ptpn11 GOF mutations could increase the risk of therapy-induced malignancies.

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Section: Ptpn11 D61g Mutation Induces Chromosomal Instability and Incsupporting

confidence: 70%

mentioning

confidence: 99%

Gain-of-function mutations of Ptpn11 (Shp2) cause aberrant mitosis and increase susceptibility to DNA damage-induced malignancies

Liu

Zheng

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…M cortisol, 10 ng/ml murine recombinant IL-3 (Peprotech), 20 ng/ml IL-6 (Peprotech), 2 U/ml erythropoietin, 20 ng/ml thrombopoietin (Peprotech), and 50 ng/ml Flt3 ligand (Peprotech) at 37°C for 57 h and then treated with 0.1 g/ml Colcemid for 3 h. For metaphase chromosome counts, thymocytes were cocultured with OP9/DL stromal cells overnight and then treated with 0.1 g/ml Colcemid for 3 h. Metaphase spreads were prepared as described previously (28). Images of chromosomes were obtained using a Nikon C2ϩ confocal microscope.…”

Section: ϫ6mentioning

confidence: 99%

Chromosome Instability Underlies Hematopoietic Stem Cell Dysfunction and Lymphoid Neoplasia Associated with Impaired Fbw7-Mediated Cyclin E Regulation

Siu

Swartz

et al. 2014

Molecular and Cellular Biology

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The Fbw7 ubiquitin ligase critically regulates hematopoietic stem cell (HSC) function, though the precise contribution of individual substrate ubiquitination pathways to HSC homeostasis is unknown. In the work reported here, we used a mouse model in which we introduced two knock-in mutations (T74A and T393A [changes of T to A at positions 74 and 393]) to disrupt Fbw7-dependent regulation of cyclin E, its prototypic substrate, and to examine the consequences of cyclin E dysregulation for HSC function. Serial transplantation revealed that cyclin E T74A T393A HSCs self-renewed normally; however, we identified defects in their multilineage reconstituting capacity. By inducing hematologic stress, we exposed an impaired self-renewal phenotype in cyclin E knock-in HSCs that was associated with defective cell cycle exit and the emergence of chromosome instability (CIN). Importantly, p53 deletion induced both defects in self-renewal and multilineage reconstitution in cyclin E knock-in HSCs with serial transplantation and CIN in hematopoietic stem and progenitor cells. Moreover, CIN was a feature of fatal T-cell malignancies that ultimately developed in recipients of cyclin E T74A T393A ; p53-null HSCs. Together, our findings demonstrate the importance of Fbw7-dependent cyclin E control to the hematopoietic system and highlight CIN as a characteristic feature of HSC dysfunction and malignancy induced by deregulated cyclin E.

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“…Furthermore, mice with conditional knock-in of the mutant PTPN11 exhibit aberrant activation of haematopoietic cells and progress to acute leukaemia. It also appears that PTPN11 mutations have non-lineage-specific effects on leukaemogenesis as tissue-specific knock-in of mutant PTPN11 results in lineage-specific leukaemia such as AML, B-cell ALL and T-cell ALL (Xu et al, 2011). One study has implicated the involvement of ROS in PTPN11 mutations such that mutated PTPN11 enhances ROS in myeloid progenitors but not in haematopoietic stem cells to facilitate myeloid expansion via cytokine signalling (e.g.…”

Section: Supporting Publications 2016: En-955 111mentioning

confidence: 99%

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

Choi¹,

Polcher²,

Joas³

2016

EFSA Supporting Publications

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This report presents the outcomes of a systematic review (SR) identifying the mechanisms and chemicals involved in the pathogenesis of Parkinson's disease (PD) and childhood leukaemia (CL). This work serves as a basis for defining and mapping the causal linkages between a molecular initiating event (MIE) and a final adverse outcome (AO) that are relevant for the development of a prototype adverse outcome pathway (AOP) for assessing risk factors for PD and CL. Search for literature from 1990 to present was conducted using Web of Science, PubMed and TOXNET, and relevant references were selected using established inclusion/exclusion criteria and ranked using a set of quality control factors.For PD, 7,384 individual references were identified to be relevant for PD pathogenesis and chemicals associated with PD. Dopaminergic neurodegeneration in the substantia nigra leading to locomotor deficits was identified as the AO in PD. Other identified key events in PD pathogenesis include mitochondrial dysfunction, cellular accumulation of alpha-synuclein and oxidative stress. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, rotenone and paraquat are some chemicals identified to be associated with PD pathogenesis.For CL, 1,988 individual references were identified to be relevant for CL pathogenesis and chemicals associated with CL. Chromosomal translocation, genetic damage/mutation and hyperdiploidy are considered as driving forces of CL. Except for infant leukaemia, CL pathogenesis requires a 'two-hit' model with an initiating event occurring in utero followed by a secondary hit potentially occurring after birth. Potential MIEs leading to these driving mechanisms include aberrant DNA topoisomerase II activity and erroneous DNA repair. Epigenetics appears to also play an influential role in CL pathogenesis. Benzene, bioflavonoids and organophosphates are some chemicals identified to be implicated in CL pathogenesis.The challenges of developing AOPs for these two diseases and the data gaps identified from the outcomes of this SR are also elaborated in this report. The present document has been produced and adopted by the bodies identified above as authors. This task has been carried out exclusively by the authors in the context of a contract between the European Food Safety Authority and the authors, awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors. KEY WORDSSystematic Review, Parkinson Disease, Childhood Leukaemia, Pathogenesis, Chemicals, Pesticides, Adverse Outcome Pathway SUMMARYThe aim of this project was to perform a systematic review (SR) to collect relevant publications related to the mechanisms involved in the pathogenesis of Parkinson's disease (PD)...

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Non–lineage/stage-restricted effects of a gain-of-function mutation in tyrosine phosphatase Ptpn11 (Shp2) on malignant transformation of hematopoietic cells

Abstract: A common Shp2 mutation leads to myeloproliferative disease and malignant acute leukemia in stem cells and committed progenitors, associated with Shp2 maintaining chromosomal stability

Cited by 99 publications

References 64 publications

Gain-of-function mutations of Ptpn11 (Shp2) cause aberrant mitosis and increase susceptibility to DNA damage-induced malignancies

Gain-of-function mutations of Ptpn11 (Shp2) cause aberrant mitosis and increase susceptibility to DNA damage-induced malignancies

Chromosome Instability Underlies Hematopoietic Stem Cell Dysfunction and Lymphoid Neoplasia Associated with Impaired Fbw7-Mediated Cyclin E Regulation

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

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