Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia.

Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft resource and perform integrated genomics, transcriptomics and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized phase II-like preclinical trial in patient-derived xenografts, imetelstat effectively diminishes AML burden and preferentially targets subgroups containing mutant NRAS and oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing substantial disease control in AML.

Hematopoietic stem and progenitor cell-restricted Cdx2 expression induces transformation to myelodysplasia and acute leukemia.

The caudal-related homeobox transcription factor CDX2 is expressed in leukemic cells but not during normal blood formation. Retroviral overexpression of Cdx2 induces AML in mice, however the developmental stage at which CDX2 exerts its effect is unknown. We developed a conditionally inducible Cdx2 mouse model to determine the effects of in vivo, inducible Cdx2 expression in hematopoietic stem and progenitor cells (HSPCs). Cdx2-transgenic mice develop myelodysplastic syndrome with progression to acute leukemia associated with acquisition of additional driver mutations. Cdx2-expressing HSPCs demonstrate enrichment of hematopoietic-specific enhancers associated with pro-differentiation transcription factors. Furthermore, treatment of Cdx2 AML with azacitidine decreases leukemic burden. Extended scheduling of low-dose azacitidine shows greater efficacy in comparison to intermittent higher-dose azacitidine, linked to more specific epigenetic modulation. Conditional Cdx2 expression in HSPCs is an inducible model of de novo leukemic transformation and can be used to optimize treatment in high-risk AML.

Prevalence of polycystic ovary syndrome in adolescents.

OBJECTIVE: To investigate the prevalence of polycystic ovary syndrome (PCOS) in adolescents and its association with obesity. DESIGN: Cross-sectional study using electronic medical records. SETTING: Not applicable. PATIENT(S): Adolescents aged 15-19 years (n = 137,502). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): PCOS diagnosed or defined according to National Institutes of Health (NIH) criteria. RESULT(S): The prevalence of a confirmed diagnosis of PCOS was 0.56%, which increased to 1.14% when undiagnosed cases with documented symptoms qualifying for PCOS according to NIH criteria were included. Compared with normal/underweight girls, the odds ratios (OR and 95% confidence interval [CI]) for confirmed PCOS diagnosis were 3.85 (3.04-4.88), 10.25 (8.16-12.84), and 23.10 (18.66-28.61) for overweight, moderately obese, and extremely obese adolescents, respectively, after adjusting for potential confounders. When adolescents with two or more supportive diagnoses were included (diagnosed and undiagnosed PCOS-NIH), the ORs (95% CI) for PCOS-NIH by weight class were significantly attenuated to 2.95 (2.53-3.44), 6.73 (5.78-7.83), and 14.65 (12.73-16.86) for overweight, moderately obese, and extremely obese adolescents, respectively. CONCLUSION(S): Overweight and obesity were associated with higher odds of PCOS in adolescents. Studies based solely on diagnosis codes may underestimate the prevalence of PCOS and overestimate the magnitude of the association between obesity and PCOS.

Pediatric idiopathic intracranial hypertension and extreme childhood obesity.

OBJECTIVE: To estimate the magnitude of the association between overweight, moderate, and extreme childhood obesity and the risk of idiopathic intracranial hypertension (IIH). STUDY DESIGN: Risk estimates were obtained from the Kaiser Permanente Southern California Children's Health Study (n = 913 178). Weight classes were assigned by body mass index specific for age and sex. A combination of electronic database searches followed by complete medical records review was used to identify all children diagnosed with IIH between 2006 and 2009. RESULTS: We identified 78 children with IIH, the majority of whom were girls (n = 66, 84.5%), age 11-19 (n = 66, 84.5%), non-Hispanic Whites (n = 37, 47.4%), and overweight or obese (n = 57, 73.1%). The adjusted ORs and 95% CIs of IIH with increasing weight class were 1.00, 3.56 (1.72-7.39), 6.45 (3.10-13.44), and 16.14 (8.18-31.85) for underweight/normal weight (reference category), overweight, moderately obese and extremely obese 11-19 year olds, respectively (P for trend < .001). Other independent IIH risk factors included White non-Hispanic race/ethnicity for all age groups and female sex, but only in older children. Overweight/obese children also had more IIH symptoms at onset than normal weight children. CONCLUSIONS: We found that childhood obesity is strongly associated with an increased risk of pediatric IIH in adolescents. Our findings suggest that the childhood obesity epidemic is likely to lead to increased morbidity from IIH particularly among extremely obese, White non-Hispanic teenage girls. Our findings also suggest careful screening of these at risk individuals may lead to earlier detection and opportunity for treatment of IIH.

Extreme childhood obesity is associated with increased risk for gastroesophageal reflux disease in a large population-based study.

OBJECTIVE: Gastroesophageal reflux disease (GERD) may link the obesity epidemic to an array of adverse health outcomes including chronic esophageal inflammation and, consequentially, to pathophysiological changes of the esophagus. Although obesity and GERD are associated in adults, data in children are scarce and inconclusive. The aim of this study is to investigate whether, similar to adults, obesity is associated with GERD in youth. METHODS: For this population-based, cross-sectional study, measured weight and height and diagnosis of GERD were extracted from electronic medical records of 690 321 patients, aged 2-19 years, who were enrolled in an integrated prepaid health plan between 2007 and 2008. Weight class (normal weight, overweight, moderate and extreme obesity) was assigned based on body mass index-for-age. RESULTS: Overall, GERD was diagnosed in 1.5% of boys and 1.8% of girls (P<0.001). Moderately and extremely obese children, aged 6-11 years, were more likely to have a diagnosis of GERD compared with normal weight (OR 1.16, 95% CI: 1.02-1.32 and 1.32, 95% CI: 1.13-1.56, respectively). Children aged 12-19 years showed similar associations (OR 1.16, 95% CI: 1.07-1.25 and 1.40, 95% CI: 1.28-1.52, respectively). These associations remained with adjustment for sex and race/ethnicity. By contrast, obesity was not related to increased odds for GERD in children aged 2-5 years of age. CONCLUSIONS: The association between childhood obesity and GERD may have important implications for their future risk of GERD-associated diseases, such as esophageal adenocarcinoma.