The PRKAA1/AMPKα1 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential target in CMML

Obba, Sandrine; Hizir, Zoheir; Boyer, Laurent; Selimoglu-Buet, Dorothée; Pfeifer, Anja; Michel, Grégory; Hamouda, Mohamed-Amine; Gonçalves, Débora Farina; Cerezo, Michaël; Marchetti, Sandrine; Droin, Nathalie; Cluzeau, Thomas; Robert, Guillaume; Luciano, Fréderic; Robaye, Bernard; Foretz, Marc; Viollet, Benoı̂t; Legros, Laurence; Solary, Éric; Auberger, Patrick; Jacquel, Arnaud

doi:10.1080/15548627.2015.1034406

Cited by 91 publications

(77 citation statements)

References 45 publications

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“…41,42 In addition to its capacity to potently inhibit JAK2 and FLT3, pacritinib is an attractive therapeutic because of its inhibitory effects on other deregulated pathways in CMML, such as those associated with CSF1R and IRAK1, both targets of pacritinib. [43][44][45] Short-term culture of BM MNCs from CMML patients ( Figure 4A; supplemental Table 1) in vehicle or increasing doses of pacritinib revealed effective CMML cell killing upon 48 hours of pacritinib exposure with a median half maximal inhibitory concentration of 339 nM (range 2.4-1363 nM) across 10 individual CMML patients ( Figure 4B). Cell death occurred via apoptosis as was evident from dose-dependent increases in apoptotic and necrotic cells ( Figure 4C).…”

Section: Jak2/flt3 Inhibition Reduces Cmml Clonogenicity In Vitro Andmentioning

confidence: 99%

Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML

Yoshimi

Balasis

Vedder

et al. 2017

Blood

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• Genetically accurate xenografts of CMML are achievable with near 100% frequency in NSGS mice.• Robust human engraftment and overt phenotypes of CMML and JMML xenografts here facilitate preclinical therapeutic evaluation in vivo.Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap disorders characterized by monocytosis, myelodysplasia, and a characteristic hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Currently, there are no available disease-modifying therapies for CMML, nor are there preclinical models that fully recapitulate the unique features of CMML. Through use of immunocompromised mice with transgenic expression of human GM-CSF, interleukin-3, and stem cell factor in a NOD/SCID-IL2Rg null background (NSGS mice), we demonstrate remarkable engraftment of CMML and JMML providing the first examples of serially transplantable and genetically accurate models of CMML. Xenotransplantation of CD34 1 cells (n 5 8 patients) or unfractionated bone marrow (BM) or peripheral blood mononuclear cells (n 5 10) resulted in robust engraftment of CMML in BM, spleen, liver, and lung of recipients (n 5 82 total mice). Engrafted cells were myeloid-restricted and matched the immunophenotype, morphology, and genetic mutations of the corresponding patient. Similar levels of engraftment were seen upon serial transplantation of human CD34 1 cells in secondary NSGS recipients (2/5 patients, 6/11 mice), demonstrating the durability of CMML grafts and functionally validating CD34 1 cells as harboring the disease-initiating compartment in vivo.Successful engraftments of JMML primary samples were also achieved in all NSGS recipients (n 5 4 patients, n 5 12 mice). Engraftment of CMML and JMML resulted in overt phenotypic abnormalities and lethality in recipients, which facilitated evaluation of the JAK2/FLT3 inhibitor pacritinib in vivo. These data reveal that NSGS mice support the development of CMML and JMML disease-initiating and mature leukemic cells in vivo, allowing creation of genetically accurate preclinical models of these disorders. (Blood. 2017;130(4):397-407)

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Section: Jak2/flt3 Inhibition Reduces Cmml Clonogenicity In Vitro Andmentioning

confidence: 99%

Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML

Yoshimi

Balasis

Vedder

et al. 2017

Blood

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“…Under stress, autophagy can provide energy and protect cells (21). To investigate whether DCN protects the cells by regulating autophagy, NCM460 cells were transfected with DCN expression plasmid, cultured under oxygen glucose deprivation (OGD) conditions and treated with autophagy inhibitor 3-MA (5 µM).…”

Section: Resultsmentioning

confidence: 99%

Expression of decorin in intestinal tissues of mice with inflammatory bowel disease and its correlation with autophagy

Zhao

Wei

et al. 2016

Experimental and Therapeutic Medicine

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The aim of this study was to investigate the expression of decorin (DCN) in the intestinal tissues of mice with inflammatory bowel disease (IBD) and its correlation with autophagy. The IBD mouse model was created by intrarectal injection of trinitrobenzene sulfonic acid. The pathology of colon tissues of the mice was examined using hematoxylin and eosin staining. Expression of DCN and the proteins associated with autophagy was detected using immunohistochemistry. Normal human colon mucosal epithelial cells (NCM460 cells) were transfected with DCN expression plasmid and the expression of DCN and autophagy-associated proteins was detected by western blot analysis. Cell apoptosis was studied using an Annexin V apoptosis detection assay and intracellular autophagosomes were observed using electron microscopy. The IBD mouse model was successfully established. Thickening, edema and inflammatory cell infiltration of the intestinal wall were observed in the IBD mice. The expression of DCN as well as the autophagy-associated proteins beclin 1 and LC3B, was increased in the intestinal tissues of the IBD mice. Furthermore, in the NCM460 cells transfected with DCN, the expression of beclin 1 and LC3B was upregulated, while p62 expression was downregulated. Intracellular autophagosomes were increased and apoptosis was decreased in the cells with DCN overexpression. Inhibition of autophagy reversed the effects of DCN on apoptosis. Therefore, DCN is able to induce autophagy and protect intestinal cells during the occurrence and development of IBD.

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“…Nevertheless, different AMPKα1 functionality in tumorigenesis has been reported, revealing a versatile role of AMPKα1 that depends on tumor types and pathological phases. Notably, forced elevation of AMPKα1 expression exhibits potent impacts in triggering protective autophagy in chronic myelomonocytic leukemia cells, therefore enhancing its anti-apoptotic ability and longevity [17]. Similarly, amplified AMPKα1 expression has been also confirmed among cervical cancer, positively correlated to tumor progression and multiplicity.…”

Section: Functions Of Ampk Signaling Components In Tumorigenesismentioning

confidence: 99%

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

Cheng

Zhang

et al. 2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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AMP-activated protein kinase (AMPK) is a ubiquitously expressed metabolic sensor among various species. Specifically, cellular AMPK is phosphorylated and activated under certain stressful conditions, such as energy deprivation, in turn to activate diversified downstream substrates to modulate the adaptive changes and maintain metabolic homeostasis. Recently, emerging evidences have implicated the potential roles of AMPK signaling in tumor initiation and progression. Nevertheless, a comprehensive description on such topic is still in scarcity, especially in combination of its biochemical features with mouse modeling results to elucidate the physiological role of AMPK signaling in tumorigenesis. Hence, we performed this thorough review by summarizing the tumorigenic role of each component along the AMPK signaling, comprising of both its upstream and downstream effectors. Moreover, their functional interplay with the AMPK heterotrimer and exclusive efficacies in carcinogenesis were chiefly explained among genetically altered mice models. Importantly, the pharmaceutical investigations of AMPK relevant medications have also been highlighted. In summary, in this review, we not only elucidate the potential functions of AMPK signaling pathway in governing tumorigenesis, but also potentiate the future targeted strategy aiming for better treatment of aberrant metabolism-associated diseases, including cancer.

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The PRKAA1/AMPKα1 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential target in CMML

Cited by 91 publications

References 45 publications

Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML

Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML

Expression of decorin in intestinal tissues of mice with inflammatory bowel disease and its correlation with autophagy

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

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