Although earlier, seminal studies demonstrated that the gut per se has the intrinsic ability to regulate the rates of iron absorption, the spotlight in the last decade has been placed on the systemic regulation of iron homeostasis by the hepatic hormone hepcidin and the molecular mechanisms that regulate its expression. Recently, however, attention has returned to the gut based on the finding that Hypoxia Inducible Factor-2 (HIF-2α) regulates the expression of key genes that contribute to iron absorption. Here we review current understanding of the molecular mechanisms that regulate iron homeostasis in the gut by focusing on the role of HIF-2 under physiological steady-state conditions and in the pathogenesis of iron-related diseases. We also discuss implications for adapting HIF-2 based therapeutic strategies in iron-related pathological conditions.

Blinatumomab is a CD19/CD3-bispecific T cell receptor-engaging (BiTE(®)) antibody with efficacy in refractory B-precursor acute lymphoblastic leukemia (B-ALL). Some patients treated with blinatumomab and other T cell-activating therapies develop cytokine release syndrome (CRS). We hypothesized that patients with more severe toxicity may experience abnormal macrophage activation triggered by the release of cytokines by TCR-activated cytotoxic T cells engaged by BiTE(®) antibodies and leading to hemophagocytic lymphohistiocytosis (HLH). We prospectively monitored a patient during blinatumomab treatment and observed that he developed HLH. He became ill 36 hours into the infusion with fever, respiratory failure, and circulatory collapse. He developed hyperferritinemia, cytopenias, hypofibrinogenemia, and a cytokine profile diagnostic for HLH. The HLH continued to progress after discontinuation of blinatumomab; however, he had rapid improvement following IL-6 receptor-directed therapy with tocilizumab. Patients treated with T cell-activating therapies, including blinatumomab, should be monitored for HLH, and cytokine-directed therapy may be considered in cases of life-threatening CRS. (Registered on clinicaltrials.gov: NCT00103285).

We report a study of an alternative treatment schedule of imatinib (IM) in chronic myeloid leukemia (CML). Seventy-six Philadelphia-positive (Ph+) - BCR-ABL - positive patients aged 65 years or older, who had been treated with IM for more than two years and who were in stable complete cytogenetic response (CCgR) and in major molecular response (MMR), were enrolled in a single-arm study to test the effects of a policy of intermittent imatinib (INTERIM) therapy, one month on and one month off. With a minimum follow-up of four years, 13 patients (17%) lost CCgR and MMR, and 14 (18 %) lost MMR only. All these patients resumed continuous imatinib, and all - but one (lost to follow-up) regained CCgR and MMR. No patients progressed to accelerated or blastic phase, or developed clonal chromosomal abnormalities in Ph+ cells, or BCR-ABL mutations. In elderly Ph+ CML patients carefully selected for a stable CCgR (lasting > 2 years), the policy of intermittent imatinib treatment affected the markers of residual disease, but not the clinical outcomes (overall and progression-free survival). ClinicalTrials.gov number: NCT 00858806.

Hematopoietic stem cells self-renew for life in order to guarantee the continuous supply of all blood cell lineages. Here we show that Poly(ADP-ribose) polymerase-2 (Parp-2) plays an essential role in hematopoietic stem/progenitor cells (HSPC) survival under steady-state conditions and in response to stress. Increased levels of cell death were observed in HSPC from untreated Parp-2(-/-) mice, but this deficit was compensated by increased rates of self-renewal, associated with impaired reconstitution of hematopoiesis upon serial bone marrow transplantation. Cell death after γ-irradiation correlated with an impaired capacity to repair DNA damage in the absence of Parp-2. Upon exposure to sublethal doses of γ-irradiation, Parp-2(-/-) mice exhibited bone-marrow failure that correlated with reduced long-term repopulation potential of irradiated Parp-2(-/-) HSPC under competitive conditions. In line with a protective role of Parp-2 against irradiation-induced apoptosis, loss of p53 or the pro-apoptotic BH3-only protein Puma restored survival of irradiated Parp-2(-/-) mice, while loss of Noxa had no such effect. Our results show that Parp-2 plays essential roles in the surveillance of genome integrity of HSPC by orchestrating DNA-repair and restraining p53-induced and Puma-mediated apoptosis. The data might impact on the design of drugs targeting Parp proteins and on the improvement of radiotherapy-based therapeutic strategies.