A novel vitamin D gene therapy for acute myeloid leukemia

Xu, Yi; Payne, Kimberly J.; Pham, Linh; Park, Eunwoo; Xiao, Jeffrey; Chi, David; Lyu, Justin; Campion, Rosalia De Necochea; Wasnik, Samiksha; Jeong, Il Seok Daniel; Tang, Xiaolei; Baylink, David J.; Chen, Chien Shing; Reeves, Mark E.; Akhtari, Mojtaba; Mirshahidi, Saied; Marcucci, Guido; Cao, Huynh

doi:10.1016/j.tranon.2020.100869

Cited by 12 publications

(8 citation statements)

References 38 publications

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“…Through in vitro studies with different cell lines, multiple pathways and signals are proof related to AML cell differentiation and can be affected by VDR [ 123 , 124 ]. These were also proofed in some in vivo studies with mice and further confirmed the possibility of increasing survival within mice [ 125 , 126 , 127 , 128 , 129 ]. Regarding clinical experience, there was no inspiring development in this field.…”

Section: Application Of Natural Products In Aml Therapymentioning

confidence: 54%

“…However, the limitation of vitamin D-affect therapy is the need for high concentration of vitamin D to reach therapeutic effect, which might cause systemic side effects [ 134 , 135 , 136 ]. Several methods are possible to overcome the barriers we face currently, including possible oral supplementation [ 132 ], select patient according to receptor polymorphisms [ 137 ], gene therapy involving CYP27B1 treatment [ 126 ].…”

Section: Application Of Natural Products In Aml Therapymentioning

confidence: 99%

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Targeting the Tumor Microenvironment in Acute Myeloid Leukemia: The Future of Immunotherapy and Natural Products

et al. 2022

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The tumor microenvironment (TME) plays an essential role in the development, proliferation, and survival of leukemic blasts in acute myeloid leukemia (AML). Within the bone marrow and peripheral blood, various phenotypically and functionally altered cells in the TME provide critical signals to suppress the anti-tumor immune response, allowing tumor cells to evade elimination. Thus, unraveling the complex interplay between AML and its microenvironment may have important clinical implications and are essential to directing the development of novel targeted therapies. This review summarizes recent advancements in our understanding of the AML TME and its ramifications on current immunotherapeutic strategies. We further review the role of natural products in modulating the TME to enhance response to immunotherapy.

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Section: Application Of Natural Products In Aml Therapymentioning

confidence: 54%

Section: Application Of Natural Products In Aml Therapymentioning

confidence: 99%

Targeting the Tumor Microenvironment in Acute Myeloid Leukemia: The Future of Immunotherapy and Natural Products

et al. 2022

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“…Some of the earliest life forms such as phytoplankton took advantage of sunlight to photosynthesize 2 metabolites for energy and survival: glucose and vitamin D [ 8 ]. Our recent study demonstrated that the combination of 1,25VD3 and 5-Azacytidine (a FDA-approved hypomethylating agent) enhanced cytotoxicity/differentiation and inhibited proliferation of AML blasts in vivo [ 9 ]. Up to 35% of AML patients have mutations in the FMS-like receptor tyrosine kinase 3 (FLT3) gene and defective protein products (AML-FLT3) that are associated with poorer survival through an increased risk of relapse [ 10 ].…”

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confidence: 99%

“…First, we performed transcriptome analyses (RNA-seq) of 4 different AML-FLT3 cell lines including MV4–11, MOLM-14, MV4–11-midostaurin-resistant cells and MOLM-14-midostaurin-resistant cells which were previously reported [ 9 ]. Among many differential expression methods developed for RNA-seq data analyses, FPKM number was found to be one of the best approaches in precision and accuracy on reporting RNA-seq results [ 16 ].…”

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confidence: 99%

Vitamin D activates FBP1 to block the Warburg effect and modulate blast metabolism in acute myeloid leukemia

Hino

Baylink

et al. 2022

Biomark Res

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Acute myeloid leukemia (AML) has the lowest survival rate among the leukemias. Targeting intracellular metabolism and energy production in leukemic cells can be a promising therapeutic strategy for AML. Recently, we presented the successful use of vitamin D (1,25VD3) gene therapy to treat AML mouse models in vivo. In this study, recognizing the importance of 1,25VD3 as one of only 2 molecules (along with glucose) photosynthesized for energy during the beginning stage of life on this planet, we explored the functional role of 1,25VD3 in AML metabolism.Transcriptome database (RNA-seq) of four different AML cell lines revealed 17,757 genes responding to 1,25VD3-treatment. Moreover, we discovered that fructose-bisphosphatase 1 (FBP1) noticeably stands out as the only gene (out of 17,757 genes) with a 250-fold increase in gene expression, which is known to encode the key rate-limiting gluconeogenic enzyme fructose-1,6-bisphosphatase. The significant increased expression of FBP1 gene and proteins induced by 1,25VD3 was confirmed by qPCR, western blot, flow cytometry, immunocytochemistry and functional lactate assay. Additionally, 1,25VD3 was found to regulate different AML metabolic processes including gluconeogenesis, glycolysis, TCA, de novo nucleotide synthesis, etc. In summary, we provided the first evidence that 1,25 VD3-induced FBP1 overexpression might be a novel therapeutic target to block the “Warburg Effect” to reduce energy production in AML blasts.

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“…27 This is consistent with data we observed in our study that SLE patients presenting with more severe COVID-19 chest symptoms had lower levels of vitamin D. The critical role of vitamin D can be also observed in certain malignancies, and vitamin D requires CYP27B1 to create active vitamin D. In a study of type of bone marrow (BM) malignancy cells, the authors noticed considerably minimal levels of CYP27B1 proteins within BM cells compared to non-AML individuals. 43 Current guidelines have suggested a target level of 30 to 40 ng/mL for cases with a possibility of fractures, falling, autoimmune disorders, and malignant tumors. The recommended dose of vitamin D therapy is <10,000 IU per day with a target 25-hydroxyvitamin D level of 30 ng/mL or more for affected cases.…”

Section: Discussionmentioning

confidence: 99%

Impact of vitamin D level and supplementation on systemic lupus erythematosus patients during COVID-19 pandemic

Adel

Elgamal

Abdelsalam³

2022

Arch Rheumatol

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Objectives: In this study, we aimed to assess the impact of serum vitamin D level in systemic lupus erythematosus (SLE) patients with novel coronavirus-2019 (COVID-19) disease on severity of infection, duration of COVID-19 disease course, and fatigue development as a complication of both SLE and COVID-19. Patients and methods: Between April 2020 and January 2021, a total of 38 patients (31 males, 7 females; mean age: 49.2±8.1 years; range, 38 to 65 years) who were previously diagnosed with SLE and on different lines of lupus management were included. The patients presented to chest outpatient clinic and emergency hospital with manifestations suggesting COVID-19 infection. Vitamin D levels were measured in serum by enzymelinked immunosorbent assay (ELISA). Vitamin D supplement was added to treatment protocols for COVID-19. Results: Thirteen (34.2%) patients had normal baseline serum vitamin D levels (≥30 ng/mL), nine (23.7%) patients had vitamin D insufficiency (21 to 29 ng/mL), and 16 (42.1%) patients had vitamin D deficiency (≤20 ng/mL). Low vitamin D levels (insufficiency & deficiency) patients had long SLE disease duration (p=0.06). Also, there was a significant long time spent until recovery from COVID-19 infection in low vitamin D levels (insufficiency & deficiency) patient groups versus those with normal vitamin D (p=0.019). Low baseline vitamin D level patients mainly presented with severe COVID19 symptoms (p=0.04). Patients recovered from COVID-19 had normal vitamin D levels than those who died or were lost to follow-up (p=0.07). After recovery from COVID-19, fatigue was more common in SLE patients with low baseline vitamin D level. Conclusion: Vitamin D seems to play a certain role in the management of COVID-19 infection in SLE patients. Patients with normal vitamin D levels have less severe symptoms, shorter time to recovery, improved COVID-19 outcomes, and less development of fatigue after COVID-19 infection.

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A novel vitamin D gene therapy for acute myeloid leukemia

Cited by 12 publications

References 38 publications

Targeting the Tumor Microenvironment in Acute Myeloid Leukemia: The Future of Immunotherapy and Natural Products

Targeting the Tumor Microenvironment in Acute Myeloid Leukemia: The Future of Immunotherapy and Natural Products

Vitamin D activates FBP1 to block the Warburg effect and modulate blast metabolism in acute myeloid leukemia

Impact of vitamin D level and supplementation on systemic lupus erythematosus patients during COVID-19 pandemic

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