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.

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 IntroductionAnemia of inflammation (AI), also known as anemia of chronic disease (ACD), is the most prevalent form of anemia after iron-deficient anemia (IDA). 1,2 AI frequently occurs in patients with a broad array of infectious, autoimmune, or inflammatory disorders, as well as cancer and kidney disease, and can contribute to the morbidity associated with these conditions. 3 In contrast to IDA, AI is typically normochromic and normocytic with hemoglobin (Hb) levels greater than 8 g/dL; however, severe AI can lead to microcytosis. 1,2 Patients with AI have diminished serum iron levels and transferrin saturations, whereas ferritin levels are normal or elevated. 3 Erythropoietin levels are typically elevated, but lower than those seen in patients with a similar degree of anemia attributable to iron deficiency. While a mild degree of anemia may be tolerated in patients who are otherwise healthy, anemia in patients with cardiovascular or pulmonary disease can impair systemic oxygen delivery, thereby worsening angina or dyspnea, or reducing exercise tolerance. Moreover, anemia is associated with worsened prognosis in cancer, 4 chronic kidney disease, 5-7 and congestive heart failure. 5,8,9 When treatment of the underlying disease is incomplete or not feasible, blood transfusions, erythropoiesis-stimulating agents (ESAs), and iron supplementation have been used to increase Hb levels in AI. However, there are known risks associated with blood transfusion, and iron supplementation in AI requires intravenous (IV) administration. Moreover, aggressive treatment with ESAs can increase the cardiovascular events and mortality in patients with kidney disease 10 and may accelerate tumor progression in patients with cancer. 11 Thus, additional therapeutic options are needed for patients with AI.A common feature of the disorders associated with AI is immune activation and production of inflammatory cytokines, such as IL-1␤, IL-6, TNF␣, and IFN␥. IL-6 is especially potent in regulating the expression of the peptide hormone hepcidin, a central regulator of systemic iron balance. [12][13][14][15] Hepcidin binds to and initiates degradation of ferroportin-1, the sole elemental iron exporter...

Over the past several years, acute and fatal respiratory illnesses have occurred in the habituated group of wild chimpanzees at the Mahale Mountains National Park, Tanzania. Common respiratory viruses, such as measles and influenza, have been considered possible causative agents; however, neither of these viruses had been detected. During the fatal respiratory illnesses in 2003, 2005 and 2006, regular observations on affected individuals were recorded. Cause-specific morbidity rates were 98.3, 52.4 and 33.8%, respectively. Mortality rates were 6.9, 3.2 and 4.6%; all deaths were observed in infants 2 months-2 years 9 months of age. Nine other chimpanzees have not been seen since the 2006 outbreak and are presumed dead; hence, morbidity and mortality rates for 2006 may be as high as 47.7 and 18.5%, respectively. During the 2005 and 2006 outbreaks, 12 fecal samples were collected from affected and nonaffected chimpanzees and analyzed for causative agents. Analysis of fecal samples from 2005 suggests the presence of paramyxovirus, and in 2006 a human-related metapneumovirus was detected and identified in an affected chimpanzee whose infant died during the outbreak. Our findings provide preliminary evidence that the causative agent associated with these illnesses is viral and contagious, possibly of human origin; and that, possibly more than one agent may be circulating in the population. We recommend that baseline health data be acquired and food wadge and fecal samples be obtained and bio-banked as early as possible when attempting to habituate new groups of chimpanzees or other great apes. For already habituated populations, disease prevention strategies, ongoing health monitoring programs and reports of diagnostic findings should be an integral part of managing these populations. In addition, descriptive epidemiology should be a major component of disease outbreak investigations.