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.

SUMMARY Physiological stem cell function is regulated by secreted factors produced by niche cells. In this study, we describe an unbiased approach based on differential single-cell gene expression analysis of mesenchymal osteolineage cells close to and further removed from hematopoietic stem/progenitor cells to identify candidate niche factors. Mesenchymal cells displayed distinct molecular profiles based on their relative location. Amongst the genes which were preferentially expressed in proximal cells, we functionally examined three secreted or cell surface molecules not previously connected to HSPC biology: the secreted RNase Angiogenin, the cytokine IL18 and the adhesion molecule Embigin and discovered that all of these factors are HSPC quiescence regulators. Our proximity-based differential single cell approach therefore reveals molecular heterogeneity within niche cells and can be used to identify novel extrinsic stem/progenitor cell regulators. Similar approaches could also be applied to other stem cell/niche pairs to advance understanding of microenvironmental regulation of stem cell function.

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The likelihood of surgical delay varied substantially across physician peer groups and was associated with provider density and patient racial composition.

Use of e-cigarettes has increased dramatically in recent years around the world. The aim of this study is to provide comprehensive national estimates of e-cigarette and tobacco use among Polish youth. A national, representative school-based cross-sectional survey among students was conducted in 2016 in Poland within the Global Youth Tobacco Survey, using a standard self-administered questionnaire, sample design and data collection protocol. A total of 5,154 eligible students (51.6% boys and 48.4% girls) aged between 11-17 years completed the survey. Among them 26.9% (31.5% of boys and 21.8% of girls) were current (use at least once in the past 30 days) e-cigarette users and 20.5% (21% of boys and 19.9% of girls) were current cigarette smokers. Fourteen percent of students were dual users of conventional cigarettes and e-cigarettes. Both cigarette and e-cigarette use increased with age, rural residence, having more pocket money, and having parents or close friends who smoke. There was also a strong correlation between use of conventional cigarettes and e-cigarettes. Current e-cigarette use was 68.7% among current cigarette smokers, while current cigarette use was 54.8% among current e-cigarette users. Daily cigarette smoking among youth has decreased substantially in Poland from 24% in 1998 to 4.8% in 2016 in boys, and from 14.4% to 3.6% in girls. However, the rapid rise in e-cigarette use poses a potential danger of reversing the tobacco use trend. Continued monitoring is needed to track the use of e-cigarettes and their impact on conventional cigarette use among youth in Poland.