Article

Essential role for Ptpn11 in survival of hematopoietic stem and progenitor cells

Cancer Biology Program, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Blood (Impact Factor: 10.43). 02/2011; 117(16):4253-61. DOI: 10.1182/blood-2010-11-319517
Source: PubMed

ABSTRACT Src homology 2 domain-containing phosphatase 2 (Shp2), encoded by Ptpn11, is a member of the nonreceptor protein-tyrosine phosphatase family, and functions in cell survival, proliferation, migration, and differentiation in many tissues. Here we report that loss of Ptpn11 in murine hematopoietic cells leads to bone marrow aplasia and lethality. Mutant mice show rapid loss of hematopoietic stem cells (HSCs) and immature progenitors of all hematopoietic lineages in a gene dosage-dependent and cell-autonomous manner. Ptpn11-deficient HSCs and progenitors undergo apoptosis concomitant with increased Noxa expression. Mutant HSCs/progenitors also show defective Erk and Akt activation in response to stem cell factor and diminished thrombopoietin-evoked Erk activation. Activated Kras alleviates the Ptpn11 requirement for colony formation by progenitors and cytokine/growth factor responsiveness of HSCs, indicating that Ras is functionally downstream of Shp2 in these cells. Thus, Shp2 plays a critical role in controlling the survival and maintenance of HSCs and immature progenitors in vivo.

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    • "Deletion of a conditional allele of Ptpn11 in murine hematopoietic cells causes profound bone marrow (BM) aplasia, rapid loss of hematopoietic stem cells (HSC) and multi-lineage progenitors, pancytopenia and early lethality [5], [6]. Conversely, expression of leukemogenic alleles of Ptpn11, such as Ptpn11D61Y [7] or Ptpn11E76K [8], in the hematopoietic compartment results in a fatal myeloproliferative neoplasm (MPN), featuring leukocytosis, anemia and hepatosplenomegaly. "
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    ABSTRACT: Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2), encoded by PTPN11, regulates signaling networks and cell fate in many tissues. Expression of oncogenic PTPN11 in the hematopoietic compartment causes myeloproliferative neoplasm (MPN) in humans and mice. However, the stage-specific effect(s) of mutant Ptpn11 on erythroid development have remained unknown. We found that expression of an activated, leukemogenic Ptpn11 allele, Ptpn11D61Y, specifically in the erythroid lineage causes dyserythropoiesis in mice. Ptpn11D61Y progenitors produce excess cKIT+CD71+Ter119- cells and aberrant numbers of cKITl°CD71+ erythroblasts. Mutant erythroblasts show elevated activation of ERK, AKT and STAT3 in response to EPO stimulation, and MEK inhibitor treatment blocks Ptpn11D61Y-evoked erythroid hyperproliferation in vitro. Thus, the expression of oncogenic Ptpn11 causes dyserythropoiesis in a cell-autonomous manner in vivo.
    PLoS ONE 10/2014; 9(10):e109682. DOI:10.1371/journal.pone.0109682 · 3.23 Impact Factor
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    • "SHP2 expression levels are elevated in AML and are related to the hyperproliferative capacity and the degree of differentiation of primary leukemia cells (8). Animal models lacking SHP2 expression in hematopoietic tissues presented peripheral blood and bone marrow cytopenia (9,10), in addition to increased apoptosis and a reduced quiescence and repopulation capacity of hematopoietic stem cells (10). SHP2 knockdown in normal human cord blood CD34+ cells strongly inhibited cell survival, proliferation, and differentiation in response to growth factor stimuli (11). "
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    ABSTRACT: The aim of this study was to evaluate the expression of protein tyrosine kinase 2 and protein tyrosine phosphatase non-receptor type 11, which respectively encode focal adhesion kinase protein and src homology 2 domain-containing protein-tyrosine phosphatase 2, in hematopoietic cells from patients with myelodysplastic syndromes. Protein tyrosine kinase 2 and tyrosine phosphatase non-receptor type 11 expressions were analyzed by quantitative polymerase chain reaction in bone marrow cells from patients with myelodysplastic syndromes and healthy donors. Protein tyrosine kinase 2 and tyrosine phosphatase non-receptor type 11 expressions did not significantly differ between normal cells and myelodysplastic cells. Our data suggest that despite the relevance of focal adhesion kinase and src homology 2 domain-containing protein-tyrosine phosphatase 2 in hematopoietic disorders, their mRNA expression do not significantly differ between total bone marrow cells from patients with myelodysplastic syndromes and healthy donors.
    Clinics (São Paulo, Brazil) 10/2013; 68(10):1371-5. DOI:10.6061/clinics/2013(10)13 · 1.42 Impact Factor
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    • "Moreover, the contribution from these mutant ES cells to erythroid, myeloid, or lymphoid cells in the chimeric mice generated from mutant ES cells was undetectable [11], [12]. Recent studies [13], [14] have confirmed that Shp2 is critical for the survival and maintenance of hematopoietic stem cells and immature progenitors. Depletion of Shp2 from adult mice resulted in rapid loss of stem cells and progenitors of all hematopoietic lineages [13], [14]. "
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    ABSTRACT: Gain of function (GOF) mutations in protein tyrosine phosphatase Ptpn11 have been identified in childhood leukemias, and these mutations are sufficient to drive the development of myeloproliferative disorder and malignant leukemias in mice. However, the molecular mechanisms by which Ptpn11 mutations induce these malignancies are not completely understood. Here we report that Ptpn11 GOF mutations cause cytokine hypersensitivity in hematopoietic cells partly by enhancing the production of reactive oxygen species (ROS). GOF mutations D61G or E76K in Ptpn11 increased ROS levels in myeloid progenitors but not in hematopoietic stem cells. Increased ROS enhanced cellular responses to cytokines by promoting cytokine signaling. Treatment with an antioxidant partially corrected cytokine hypersensitivity in Ptpn11 mutant progenitors. Further analyses demonstrated that Ptpn11 mutations increased mitochondrial aerobic metabolism by interacting with a novel substrate in the mitochondria. This study provides new insights into the pathogenic effects of GOF mutations of Ptpn11 and implies that antioxidants may have a therapeutic benefit for the leukemic patients with these mutations.
    PLoS ONE 05/2013; 8(5):e63152. DOI:10.1371/journal.pone.0063152 · 3.23 Impact Factor
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