Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Type of study
Language
Publication year range
1.
Cell ; 167(1): 171-186.e15, 2016 Sep 22.
Article in English | MEDLINE | ID: mdl-27641501

ABSTRACT

While acute myeloid leukemia (AML) comprises many disparate genetic subtypes, one shared hallmark is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Therapies that overcome differentiation arrest represent a powerful treatment strategy. We leveraged the observation that the majority of AML, despite their genetically heterogeneity, share in the expression of HoxA9, a gene normally downregulated during myeloid differentiation. Using a conditional HoxA9 model system, we performed a high-throughput phenotypic screen and defined compounds that overcame differentiation blockade. Target identification led to the unanticipated discovery that inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) enables myeloid differentiation in human and mouse AML models. In vivo, DHODH inhibitors reduced leukemic cell burden, decreased levels of leukemia-initiating cells, and improved survival. These data demonstrate the role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a strategy for overcoming differentiation blockade in AML.


Subject(s)
Antineoplastic Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Molecular Targeted Therapy , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Cell Differentiation , Dihydroorotate Dehydrogenase , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/isolation & purification , High-Throughput Screening Assays , Homeodomain Proteins/genetics , Humans , Leukemia, Myeloid, Acute/genetics , Mice , Myeloid Cells/pathology , Oxidoreductases Acting on CH-CH Group Donors/metabolism , Pyrimidines/metabolism , Small Molecule Libraries/chemistry , Small Molecule Libraries/isolation & purification , Small Molecule Libraries/therapeutic use , Xenograft Model Antitumor Assays
2.
Blood ; 117(18): 4915-23, 2011 May 05.
Article in English | MEDLINE | ID: mdl-21393479

ABSTRACT

Anemia of inflammation develops in settings of chronic inflammatory, infectious, or neoplastic disease. In this highly prevalent form of anemia, inflammatory cytokines, including IL-6, stimulate hepatic expression of hepcidin, which negatively regulates iron bioavailability by inactivating ferroportin. Hepcidin is transcriptionally regulated by IL-6 and bone morphogenetic protein (BMP) signaling. We hypothesized that inhibiting BMP signaling can reduce hepcidin expression and ameliorate hypoferremia and anemia associated with inflammation. In human hepatoma cells, IL-6-induced hepcidin expression, an effect that was inhibited by treatment with a BMP type I receptor inhibitor, LDN-193189, or BMP ligand antagonists noggin and ALK3-Fc. In zebrafish, the induction of hepcidin expression by transgenic expression of IL-6 was also reduced by LDN-193189. In mice, treatment with IL-6 or turpentine increased hepcidin expression and reduced serum iron, effects that were inhibited by LDN-193189 or ALK3-Fc. Chronic turpentine treatment led to microcytic anemia, which was prevented by concurrent administration of LDN-193189 or attenuated when LDN-193189 was administered after anemia was established. Our studies support the concept that BMP and IL-6 act together to regulate iron homeostasis and suggest that inhibition of BMP signaling may be an effective strategy for the treatment of anemia of inflammation.


Subject(s)
Anemia/etiology , Anemia/prevention & control , Bone Morphogenetic Proteins/antagonists & inhibitors , Inflammation/complications , Animals , Antimicrobial Cationic Peptides/metabolism , Bone Morphogenetic Protein Receptors, Type I/antagonists & inhibitors , Carrier Proteins/pharmacology , Hematopoietic Stem Cells/drug effects , Hep G2 Cells , Hepcidins , Humans , Interleukin-6/pharmacology , Mice , Mice, Inbred C57BL , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Recombinant Proteins/pharmacology , Signal Transduction/drug effects , Turpentine/toxicity , Zebrafish , Zebrafish Proteins/metabolism
3.
Am J Primatol ; 72(7): 566-74, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20146237

ABSTRACT

Although the intestinal flora of chimpanzees has not been studied, insight into this dynamic environment can be obtained through studies on their feces. We analyzed fecal samples from human-habituated, wild chimpanzees at Mahale Mountains National Park, Tanzania, and compared microbial community profiles to determine if members of the same social group were similar. Between July and December 2007, we collected fresh fecal samples from 12 individuals: four juveniles, four adolescents, and four adults, including three parent-offspring pairs. Each sample was analyzed using Terminal-Restriction Fragment Length Polymorphism of amplified 16S rRNA genes. Twelve different profiles were generated, having between 1 and 15 Terminal-Restriction Fragments (T-RFs). Overall, a total of 23 different T-RFs were produced. Putative assignments of T-RFs corresponded to the phyla Firmicutes (Clostridia, Bacilli, and Lactobacilli), Bacteroidetes, Tenericutes (Mollicutes Class), Actinobacteria, and Proteobacteria, as well as to uncultured or unidentified organisms. Firmicutes and Bacteroidetes phyla and Mollicutes Class were the most commonly assigned in 11, 8, and 8 of the samples, respectively, with this being the first report of Mollicutes in wild chimpanzees. Principal Components Analysis (PCA) revealed clustering of nine samples, and 80.5% of the diversity was accounted for by three samples. Morisita indices of community similarity ranged between 0.00 and 0.89, with dissimiliarity (<0.5) between most samples when compared two at a time. Our findings suggest that, although phylotypes are common among individuals, profiles among members of the same social group are host-specific. We conclude that factors other than social group, such as kinship and age, may influence fecal bacterial profiles of wild chimpanzees, and recommend that additional studies be conducted.


Subject(s)
Feces/microbiology , Gram-Positive Bacteria/genetics , Pan troglodytes/microbiology , Animal Feed , Animals , Deoxyribonucleases, Type II Site-Specific/genetics , Female , Fruit , Gram-Positive Bacteria/isolation & purification , Habituation, Psychophysiologic , Humans , Male , Pan troglodytes/genetics , Pan troglodytes/growth & development , Pan troglodytes/psychology , Plant Leaves , Polymerase Chain Reaction/methods , Polymorphism, Restriction Fragment Length , RNA, Bacterial/genetics , RNA, Ribosomal, 16S/genetics , Social Behavior , Tanzania
SELECTION OF CITATIONS
SEARCH DETAIL
...