Functional Network Reconstruction Reveals Somatic Stemness Genetic Maps and Dedifferentiation-Like Transcriptome Reprogramming Induced by GATA2

Huang, Tsung Hui; Hsieh, Jui Yu; Wu, Yu-Hsueh; Jen, Chih Hung; Tsuang, Yang Hwei; Chiou, Shih Hwa; Partanen, Jukka; Anderson, Heidi; Jaatinen, Taina; Yu, Yau Hua; Wang, Hsei Wei

doi:10.1634/stemcells.2007-0821

Cited by 44 publications

(48 citation statements)

References 71 publications

(113 reference statements)

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“…A recent gene expression microarray and systems biology study showed that SHP-2 (PTPN11), like GATA2, PTEN, and STAT5, acted as a hub to maintain the stability and connectivity of the whole genetic network in human HSCs. 47 Shp-2 is known to be involved in the signal transduction of multiple cytokines and growth factors, and it plays an overall positive role in the signaling processes. [13][14][15] GOF mutations in Ptpn11, including D61G mutation, may disturb HSC function by altering cytokine or growth factor signaling.…”

Section: Discussionmentioning

confidence: 99%

A germline gain-of-function mutation in Ptpn11 (Shp-2) phosphatase induces myeloproliferative disease by aberrant activation of hematopoietic stem cells

Wang

et al. 2010

Blood

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Germline and somatic gain-of-function mutations in tyrosine phosphatase PTPN11 (SHP-2) are associated with juvenile myelomonocytic leukemia (JMML), a myeloproliferative disease (MPD) of early childhood. The mechanism by which PTPN11 mutations induce this disease is not fully understood. Signaling partners that mediate the pathogenic effects of PTPN11 mutations have not been explored. Here we report that germ line mutation Ptpn11 D61G in mice aberrantly accelerates hematopoietic stem cell (HSC) cycling, increases the stem cell pool, and elevates short-term and long-term repopulating capabilities, leading to the development of MPD. MPD is reproduced in primary and secondary recipient mice transplanted with Ptpn11 D61G/؉ whole bone marrow cells or purified Lineage ؊ Sca-1 ؉ c-Kit ؉ cells, but not lineage committed progenitors. The deleterious effects of Ptpn11 D61G mutation on HSCs are attributable to enhancing cytokine/growth factor signaling. The aberrant HSC activities caused by Ptpn11 D61G mutation are largely corrected by deletion of Gab2, a prominent interacting protein and target of Shp-2 in cell signaling. As a result, MPD phenotypes are markedly ameliorated in Ptpn11 D61G/؉ / Gab2 ؊/؊ double mutant mice. Collectively, our data suggest that oncogenic Ptpn11 induces MPD by aberrant activation of HSCs. This study also identifies Gab2 as an important mediator for the pathogenic effects of Ptpn11 mutations. (Blood. 2010;116(18): 3611-3621) IntroductionJuvenile myelomonocytic leukemia (JMML), a myeloproliferative disease (MPD) of young children characterized by cytokine hypersensitivity of myeloid progenitors, is associated with mutations in the rat sarcoma viral oncogene (RAS) pathway. 1,2 Thirtyfive percent of patients with JMML have activating mutations in tyrosine phosphatase PTPN11 (SHP-2), a known positive regulator of the Ras pathway (see next paragraph), while activating mutations in RAS (N-RAS or K-RAS) and homozygous inactivation of NF1, a GTPase activating protein that negatively regulates RAS output, account for 20% and 15% of JMML cases, respectively. 1,2 More recently, loss-of-function mutations in a E3 ubiquitin ligase c-CBL have been identified in 10%-15% of patients with JMML. 3,4 PTPN11, RAS, NF1, and c-CBL mutations are usually mutually exclusive in patients. Remarkably, mutations in these genes play a causal role in the pathogenesis of JMML. Single disease mutations, such as Ptpn11 D61G/Y , K-Ras G12D , Nf1 deficiency, and Cbl deficiency, are necessary and sufficient to induce cytokine hypersensitivity in myeloid progenitors and JMML-like MPD in mice. [5][6][7][8][9][10][11][12] Ptpn11 (Shp-2), a ubiquitously expressed protein tyrosine phosphatase, is involved in multiple cell signaling processes, such as the RAS-MAP kinase, JAK/STAT, PI3K/AKT, NF-B, and NFAT pathways. [13][14][15] Intriguingly, despite its direct function in protein dephosphorylation, Shp-2 generally plays a positive role in transducing signals initiated from receptor and cytosolic kinases. This is particularly the case for ...

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Section: Discussionmentioning

confidence: 99%

A germline gain-of-function mutation in Ptpn11 (Shp-2) phosphatase induces myeloproliferative disease by aberrant activation of hematopoietic stem cells

Wang

et al. 2010

Blood

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“…22 MSI2 has been shown to regulate pathways important for control of HSC proliferation and differentiation, including RAS, MITOGEN-ACTIVATED PROTEIN KINASE, CYCLIN D1, MYC, MEIS1, HOXA9, HOXA10, and NOTCH pathway effectors. 12,13 MSI2 expression is increased in HSCs compared with their differentiated progeny, 12,23 and its control is important in maintaining normal HSC turnover and differentiation. 12 In normal human HSCs, MSI2 is up-regulated by HOXA9, 14 of importance considering the initial discovery of MSI2 in patients with CML carrying the t(7;17)(p15;q23) translocation, which resulted in a MSl2/HOXA9 fusion gene.…”

Section: Msi2 Protein Predicts Unfavorable Outcome In Aml 2863 Bloodmentioning

confidence: 99%

MSI2 protein expression predicts unfavorable outcome in acute myeloid leukemia

Byers

Currie

Tholouli

et al. 2011

Blood

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“…Notably, GSEA revealed the gene expression signature of PHBECs cultured on coated meshes to be highly correlated with the signature of EpCAM + epithelial cells, luminal progenitor cells, and BPECs but not CD10+ myoepithelial/myofibroblast cells, basal cells or HMECs, respectively (see Additional file 4C-E) [1,63,64]. Furthermore, the gene expression signature of hAMSCs cultured in our ex vivo culture conditions, but not PHBECs, overlapped highly significantly with published MSC profiles [65,66] (see Additional file 4F, G). In summary, these data confirm that the ex vivo cell culture conditions described here maintain the epithelial and mesenchymal identities of PHBECs and hAMSCs, respectively.…”

Section: Resultsmentioning

confidence: 90%

“…For Huang et al . [65]: hAMSC: ES = 0.82, NES = 1.31, FDR = 0.092, P <0.001; PHBEC: ES = −0.82, NES = −1.3, FDR = 1.116, P <0.001.…”

Section: Supplementary Materialsmentioning

confidence: 99%

Mesenchymal precursor cells maintain the differentiation and proliferation potentials of breast epithelial cells

et al. 2014

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IntroductionStromal-epithelial interactions play a fundamental role in tissue homeostasis, controlling cell proliferation and differentiation. Not surprisingly, aberrant stromal-epithelial interactions contribute to malignancies. Studies of the cellular and molecular mechanisms underlying these interactions require ex vivo experimental model systems that recapitulate the complexity of human tissue without compromising the differentiation and proliferation potentials of human primary cells.MethodsWe isolated and characterized human breast epithelial and mesenchymal precursors from reduction mammoplasty tissue and tagged them with lentiviral vectors. We assembled heterotypic co-cultures and compared mesenchymal and epithelial cells to cells in corresponding monocultures by analyzing growth, differentiation potentials, and gene expression profiles.ResultsWe show that heterotypic culture of non-immortalized human primary breast epithelial and mesenchymal precursors maintains their proliferation and differentiation potentials and constrains their growth. We further describe the gene expression profiles of stromal and epithelial cells in co-cultures and monocultures and show increased expression of the tumor growth factor beta (TGFβ) family member inhibin beta A (INHBA) in mesenchymal cells grown as co-cultures compared with monocultures. Notably, overexpression of INHBA in mesenchymal cells increases colony formation potential of epithelial cells, suggesting that it contributes to the dynamic reciprocity between breast mesenchymal and epithelial cells.ConclusionsThe described heterotypic co-culture system will prove useful for further characterization of the molecular mechanisms mediating interactions between human normal or neoplastic breast epithelial cells and the stroma, and will provide a framework to test the relevance of the ever-increasing number of oncogenomic alterations identified in human breast cancer.

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Functional Network Reconstruction Reveals Somatic Stemness Genetic Maps and Dedifferentiation-Like Transcriptome Reprogramming Induced by GATA2

Abstract: ABSTRACT

Cited by 44 publications

References 71 publications

A germline gain-of-function mutation in Ptpn11 (Shp-2) phosphatase induces myeloproliferative disease by aberrant activation of hematopoietic stem cells

A germline gain-of-function mutation in Ptpn11 (Shp-2) phosphatase induces myeloproliferative disease by aberrant activation of hematopoietic stem cells

MSI2 protein expression predicts unfavorable outcome in acute myeloid leukemia

Mesenchymal precursor cells maintain the differentiation and proliferation potentials of breast epithelial cells

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