Prenatal vitamin D deficiency alters immune cell proportions of young adult offspring through alteration of long-term stem cell fates.

Vitamin D deficiency is a common deficiency worldwide, particularly among women of reproductive age. During pregnancy, it increases the risk of immune-related diseases in offspring later in life. However, exactly how the body remembers exposure to an adverse environment during development is poorly understood. Herein, we explore the effects of prenatal vitamin D deficiency on immune cell proportions in offspring using vitamin D deficient mice established by dietary manipulation. We show that prenatal vitamin D deficiency alters immune cell proportions in offspring by changing the transcriptional properties of genes downstream of vitamin D receptor signaling in hematopoietic stem and progenitor cells of both the fetus and adults. Further investigations of the associations between maternal vitamin D levels and cord blood immune cell profiles from 75 healthy pregnant women and their term babies also confirm that maternal vitamin D levels significantly affect immune cell proportions in the babies. Thus, lack of prenatal vitamin D, particularly at the time of hematopoietic stem cell migration from the liver to the bone marrow, has long-lasting effects on immune cell proportions. This highlights the importance of providing vitamin D supplementation at specific stages of pregnancy.

Ascorbic acid-induced TET activation mitigates adverse hydroxymethylcytosine loss in renal cell carcinoma.

Although clear cell renal cell carcinoma (ccRCC) has been shown to result in widespread aberrant cytosine methylation and loss of 5-hydroxymethylcytosine (5hmC), the prognostic impact and therapeutic targeting of this epigenetic aberrancy has not been fully explored. Analysis of 576 primary ccRCC samples demonstrated that loss of 5hmC was strongly associated with aggressive clinicopathologic features and was an independent adverse prognostic factor. Loss of 5hmC also predicted reduced progression-free survival after resection of nonmetastatic disease. The loss of 5hmC in ccRCC was not due to mutational or transcriptional inactivation of ten eleven translocation (TET) enzymes, but to their functional inactivation by l-2-hydroxyglutarate (L2HG), which was overexpressed due to the deletion and underexpression of L2HG dehydrogenase (L2HGDH). Ascorbic acid (AA) reduced methylation and restored genome-wide 5hmC levels via TET activation. Fluorescence quenching of the recombinant TET-2 protein was unaffected by L2HG in the presence of AA. Pharmacologic AA treatment led to reduced growth of ccRCC in vitro and reduced tumor growth in vivo, with increased intratumoral 5hmC. These data demonstrate that reduced 5hmC is associated with reduced survival in ccRCC and provide a preclinical rationale for exploring the therapeutic potential of high-dose AA in ccRCC.

Eltrombopag for the treatment of thrombocytopenia in patients with malignant and non-malignant hematologic disorders.

INTRODUCTION: Eltrombopag (EP) is an orally bioavailable, non-peptide, thrombopoietin receptor (TPO-R) agonist developed to stimulate platelet production. EP is a small hydrazone molecule which interacts with the transmembrane domain of TPO-R and promotes megakaryopoiesis, and a subsequent increase in platelet number. To date, multiple large clinical trials have demonstrated the ability of EP to reduce the burden of thrombocytopenia and its associated side effects in patients with chronic immune thrombocytopenia purpura and patients with hepatitis-C related thrombocytopenia. Given these promising results and the morbidity associated with thrombocytopenia in cancer patients, there is significant interest in investigating the role of EP for thrombocytopenia secondary to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). AREAS COVERED: In this review, the authors address the potential utility of EP for patients with AML and MDS with thrombocytopenia. The review provides an overview of the rationale for the development of EP in AML and MDS, and the mechanism(s) of action of EP. The authors focus on preclinical data describing the effectiveness of EP as both a platelet-stimulating, and an anti-leukemia agent and describe the use of EP in clinical trials. EXPERT OPINION: EP has the potential to be an effective supportive care agent, improving platelet counts and decreasing thrombocytopenia-related morbidity, in patients with AML and MDS. Large, randomized clinical trials are needed to assess the efficacy of EP in reducing the duration and severity of thrombocytopenia, as well assess the clinical utility of EP as an anti-leukemia agent.