Abstract
The effects of vitamin A and/or vitamin D deficiency were studied in an Arf−/− BCR-ABL acute lymphoblastic leukemia murine model. Vitamin D sufficient mice died earlier (p = 0.003) compared to vitamin D deficient (VDD) mice. Vitamin A deficient (VAD) mice fared worst with more rapid disease progression and decreased survival. Mice deficient for vitamins A and D (VADD) had disease progression similar to VAD mice. Regulatory T cells, previously shown to associate with poor BCR-ABL leukemia control, were present at higher frequencies among CD4+ splenocytes of vitamin A deficient vs. sufficient mice. In vitro studies demonstrated 1,25-dihydroxyvitamin D (1,25(OH)2VD3) increased the number of BCR-ABL ALL cells only when co-cultured with bone marrow stroma. 1,25(OH)2VD3 induced CXCL12 expression in vivo and in vitro in stromal cells and CXCL12 increased stromal migration and the number of BCR-ABL blasts. Vitamin D plus leukemia reprogrammed the marrow increasing production of collagens, potentially trapping ALL blasts. Vitamin A (all trans retinoic acid, ATRA) treated leukemic cells had increased apoptosis, decreased cells in S-phase, and increased cells in G0/G1. ATRA signaled through the retinoid X receptor to decrease BCR-ABL leukemic cell viability. In conclusion, vitamin A and D deficiencies have opposing effects on mouse survival from BCR-ABL ALL.
Highlights
Vitamin D deficiency (VDD) affects an estimated 1 billion people in the world across all ethnicities and age groups[1,2,3]
Progression of BCR-ABL Arf-/- luciferase tagged pre-B leukemia cells and survival from disease were compared between vitamin sufficient control mice and vitamin D deficient (VDD), vitamin A deficient (VAD) and vitamins A and D (VADD) mice by in vivo bioluminescence imaging of leukemic cells starting on day 8 after injection in male and female mice
Our study found mice deficient in vitamin A had markedly accelerated disease progression and decreased survival from BCR-ABL Acute lymphoblastic leukemia (ALL) compared to mice that were vitamin A sufficient
Summary
Vitamin D deficiency (VDD) affects an estimated 1 billion people in the world across all ethnicities and age groups[1,2,3]. Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer accounting for almost 80% of pediatric leukemias[14], and multiple reports suggest that a majority of leukemia patients are VD3 deficient at the time of diagnosis[5,15]. Both Dana Farber (ClinicalTrials.gov Identifier number: NCT01574274). Www.nature.com/scientificreports and Children’s Hospital of LA (Identifier number: NCT01317940) have ongoing pediatric ALL clinical trials to monitor patients’ VD3 levels and to give supplementation to restore sufficiency It is not known how VD3 deficiency or supplementation might affect ALL progression or survival. Retinoids work in part as ligands that activate a number of nuclear receptors (e.g., retinoic acid receptors (RARs), retinoid x receptors (RXRs)) depending on the cell type
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