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1.
Aging (Albany NY) ; 7(11): 911-27, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26546739

RESUMO

The TERT gene encodes for the reverse transcriptase activity of the telomerase complex and mutations in TERT can lead to dysfunctional telomerase activity resulting in diseases such as dyskeratosis congenita (DKC). Here, we describe a novel TERT mutation at position T1129P leading to DKC with progressive bone marrow (BM) failure in homozygous members of a consanguineous family. BM hematopoietic stem cells (HSCs) of an affected family member were 300-fold reduced associated with a significantly impaired colony forming capacity in vitro and impaired repopulation activity in mouse xenografts. Recent data in yeast suggested improved cellular checkpoint controls by mTOR inhibition preventing cells with short telomeres or DNA damage from dividing. To evaluate a potential therapeutic option for the patient, we treated her primary skin fibroblasts and BM HSCs with the mTOR inhibitor rapamycin. This led to prolonged survival and decreased levels of senescence in T1129P mutant fibroblasts. In contrast, the impaired HSC function could not be improved by mTOR inhibition, as colony forming capacity and multilineage engraftment potential in xenotransplanted mice remained severely impaired. Thus, rapamycin treatment did not rescue the compromised stem cell function of TERTT1129P mutant patient HSCs and outlines limitations of a potential DKC therapy based on rapamycin.


Assuntos
Antígenos CD34/análise , Senescência Celular , Disceratose Congênita/genética , Células-Tronco Hematopoéticas/fisiologia , Mutação , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Telomerase/genética , Animais , Feminino , Células HeLa , Transplante de Células-Tronco Hematopoéticas , Humanos , Camundongos , Telômero
2.
Blood ; 125(7): 1159-69, 2015 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-25538044

RESUMO

The interaction between thrombopoietin (THPO) and its receptor c-Mpl regulates downstream cytokine signaling and platelet homeostasis. Hereditary mutations of c-Mpl can either result in loss-of-function and thrombocytopenia or in gain-of-function and thrombocythemia (HT), and are important models to analyze the mechanism of c-Mpl activity. We have analyzed the effect of the c-Mpl P106L gain-of-function and the nearby loss-of-function R102P and F104S mutations, which cause HT or thrombocytopenia, respectively, on posttranslational processing, intracellular trafficking, cell surface expression, and cell proliferation. In contrast to R102P and F104S, the P106L mutant confers cytokine-independent growth and stimulates downstream signaling after THPO treatment in Ba/F3 cells. Despite their opposite function, R102P and P106L, both lead to abnormal subcellular receptor distribution, lack of membrane localization, impaired glycosylation, and elevated THPO serum levels in effected patients. These findings indicate that the activation of downstream signaling by c-Mpl P106L does not require correct processing, trafficking, and cell surface expression of c-Mpl, whereas the negative feedback loop controlling THPO serum levels requires cell surface expression of the receptor. Thus, we propose that the P106L mutation functionally separates the activity of c-Mpl in downstream signaling from that in maintaining platelet homeostasis.


Assuntos
Mutação de Sentido Incorreto , Receptores de Trombopoetina/genética , Trombocitopenia/genética , Trombopoetina/metabolismo , Adulto , Substituição de Aminoácidos , Células Cultivadas , Criança , Pré-Escolar , Família , Feminino , Células HeLa , Homeostase/genética , Humanos , Leucina/genética , Masculino , Linhagem , Prolina/genética , Receptores de Trombopoetina/fisiologia , Transdução de Sinais/genética , Trombocitopenia/metabolismo , Trombocitose/genética , Adulto Jovem
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