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Decreased autophagy contributes to malignancies; however, it is unclear how autophagy has an impact on tumor growth. Acute myeloid leukemia (AML) is an ideal model to address this as (i) patient samples are easily accessible, (ii) the hematopoietic stem and progenitor cells (HSPC) where transformation occurs is well characterized and (iii) loss of the key autophagy gene Atg7 in HSPCs leads to a lethal pre-leukemic phenotype in mice. Here we demonstrate that loss of Atg5 results in an identical HSPC phenotype as loss of Atg7, confirming a general role for autophagy in HSPC regulation. Compared with more committed/mature hematopoietic cells, healthy human and mouse HSPCs displayed enhanced basal autophagic flux, limiting mitochondrial damage and reactive oxygen species in this long-lived population. Taken together, with our previous findings these data are compatible with autophagy-limiting leukemic transformation. In line with this, autophagy gene losses are found within chromosomal regions that are commonly deleted in human AML. Moreover, human AML blasts showed reduced expression of autophagy genes and displayed decreased autophagic flux with accumulation of unhealthy mitochondria, indicating that deficient autophagy may be beneficial to human AML. Crucially, heterozygous loss of autophagy in an MLL–ENL model of AML led to increased proliferation in vitro, a glycolytic shift and more aggressive leukemias in vivo. With autophagy gene losses also identified in multiple other malignancies, these findings point to low autophagy, providing a general advantage for tumor growth.

Objectives: Hematologic and non-hematologic benefits from iron supplementation are chiefly seen in iron deficient individuals; concerns that iron might promote infection especially in non-iron deficient individuals have complicated global anemia control policies, particularly in malaria-endemic settings. Iron homeostasis, including intestinal absorption, is controlled by hepcidin. Hepcidin is regulated by iron, erythropoietic drive, and inflammation, suggesting its potential utility to appraise iron status and thus guide iron supplementation. Methods: In 1338 African pre-school children we evaluated the Area Under the ROC Curve (AUCROC) for plasma hepcidin concentration as a diagnostic test of iron status, anemia type and erythrocyte incorporation of oral iron, determining and modeling the effects of cutoffs. Results: Hepcidin detected iron deficiency with an AUCROC = 0.85 (optimal sensitivity/ specificity at a cutoff of 5.5 ng/ml); this was not significantly affected by gender, wasting, malaria or carriage of inherited red cell disorders. In anemic children, hepcidin distinguished iron deficiency anemia from anemia of inflammation (AUCROC=0.89, optimal sensitivity/specificity cutoff 5.4 ng/ml). Hepcidin was the best predictor for >20% incorporation into erythrocytes of orally-administered 57Fe (AUCROC=0.90, optimal sensitivity/ specificity cutoff P. falciparum and 86% of children with anemia of inflammation would have avoided iron. Conclusions: In African children, hepcidin ascertains iron status, distinguishes iron deficiency anemia from anemia of inflammation, and hence could guide iron supplementation toward groups in whom it will likely be beneficial and safe.

The expression of melanoma-associated antigens (MAA) being limited to normal melanocytes and melanomas, MAAs are ideal targets for immunotherapy and melanoma vaccines. As MAAs are derived from self, immune responses to these may be limited by thymic tolerance. The extent to which self-tolerance prevents efficient immune responses to MAAs remains unknown. The autoimmune regulator (AIRE) controls the expression of tissue-specific self-antigens in thymic epithelial cells (TECs). The level of antigens expressed in the TECs determines the fate of auto-reactive thymocytes. Deficiency in AIRE leads in both humans (APECED patients) and mice to enlarged autoreactive immune repertoires. Here we show increased IgG levels to melanoma cells in APECED patients correlating with autoimmune skin features. Similarly, the enlarged T cell repertoire in AIRE(-/-) mice enables them to mount anti-MAA and anti-melanoma responses as shown by increased anti-melanoma antibodies, and enhanced CD4(+) and MAA-specific CD8(+) T cell responses after melanoma challenge. We show that thymic expression of gp100 is under the control of AIRE, leading to increased gp100-specific CD8(+) T cell frequencies in AIRE(-/-) mice. TRP-2 (tyrosinase-related protein), on the other hand, is absent from TECs and consequently TRP-2 specific CD8(+) T cells were found in both AIRE(-/-) and AIRE(+/+) mice. This study emphasizes the importance of investigating thymic expression of self-antigens prior to their inclusion in vaccination and immunotherapy strategies.