Vitamin D in hematological disorders and malignancies

Kulling, Paige M.; Olson, Kristine C.; Olson, Thomas L.; Feith, David J.

doi:10.1111/ejh.12818

Cited by 69 publications

(59 citation statements)

References 82 publications

(196 reference statements)

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“…With gradual recognition of the role of vitamin D deficiency in many diseases [ 4 ], the relationship between vitamin D and iron status has also begun to be explored [ 1 ]. It has been demonstrated that a deficit of vitamin D increases the risk of many hematological disorders and iron metabolism disturbances [ 26 , 44 ], which was visible, especially in adults with different illnesses [ 26 ]. One reason for this is the pro-inflammatory effects of a vitamin D deficit, which eventually leads to an increase in hepcidin production, via stimulation of pro-inflammatory cytokines [ 31 ] and activation of the JAK-STAT3 pathway [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated that a deficit of vitamin D increases the risk of many hematological disorders and iron metabolism disturbances [ 26 , 44 ], which was visible, especially in adults with different illnesses [ 26 ]. One reason for this is the pro-inflammatory effects of a vitamin D deficit, which eventually leads to an increase in hepcidin production, via stimulation of pro-inflammatory cytokines [ 31 ] and activation of the JAK-STAT3 pathway [ 44 ]. Sun et al [ 34 ] pointed out that vitamin D can also downregulate hepcidin transcription, although the mechanism by which this occurs is unknown.…”

Section: Discussionmentioning

confidence: 99%

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The Association between Iron and Vitamin D Status in Female Elite Athletes

Malczewska-Lenczowska

Sitkowski

Surała

et al. 2018

Nutrients

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Vitamin D may influence iron metabolism and erythropoiesis, whereas iron is essential for vitamin D synthesis. We examined whether vitamin D deficiencies (VDD) are associated with reduced iron status and whether progressive iron deficiency (ID) is accompanied by inferior vitamin D status. The study included 219 healthy female (14–34 years old) athletes. VDD was defined as a 25(OH)D concentration < 75 nmol/L. ID was classified based on ferritin, soluble transferrin receptor (sTfR), total iron binding capacity (TIBC) and blood morphology indices. The percentage of ID subjects was higher (32%) in the VDD group than in the 25(OH)D sufficient group (11%) (χ2 = 10.6; p = 0.001). The percentage of VDD subjects was higher (75%) in the ID than in the normal iron status group (48%) (χ2 = 15.6; p = 0.001). The odds ratios (ORs) for VDD increased from 1.75 (95% CI 1.02–2.99; p = 0.040) to 4.6 (95% CI 1.81–11.65; p = 0.001) with progressing iron deficiency. ID was dependent on VDD in both VDD groups (25(OH)D < 75 and < 50 nmol/L). The ID group had a lower 25(OH)D concentration (p = 0.000). The VDD group had lower ferritin (p = 0.043) and iron (p = 0.004) concentrations and higher values of TIBC (p = 0.016) and sTfR (p = 0.001). The current results confirm the association between vitamin D and iron status in female athletes, although it is difficult to assess exactly which of these nutrients exerts a stronger influence over the other.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Association between Iron and Vitamin D Status in Female Elite Athletes

Malczewska-Lenczowska

Sitkowski

Surała

et al. 2018

Nutrients

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“…This causes a conformational change so VDR can bind its retinoid X receptor (RXR) binding partner, and this heterodimer moves to the nucleus to promote or repress transcription of certain genes [12]. This pathway turns off activated T cells by decreasing inflammatory cytokine production and STAT phosphorylation [13–17]. We previously showed this to be the case in T-LGLL patient peripheral blood mononuclear cells (PBMCs) in culture and in the TL-1 cell line, a model of T-LGLL [5, 18].…”

Section: Introductionmentioning

confidence: 99%

Vitamin D pathway activation selectively deactivates signal transducer and activator of transcription (STAT) proteins and inflammatory cytokine production in natural killer leukemic large granular lymphocytes

Olson

Larkin²,

Signorelli

et al. 2018

Cytokine

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Calcitriol, the active form of vitamin D, has been well documented to act directly on immune cells and malignant cells. Activated T cells are one of the best characterized targets of calcitriol, with effects including decreasing inflammatory cytokine output and promoting anti-inflammatory cytokine production. However, the effects of calcitriol on natural killer (NK) cells are less clear. Reports suggest that only immature NK cell populations are affected by calcitriol treatment resulting in impaired cytotoxic function and cytokine production, while mature NK cells may have little or no response. NK cell large granular lymphocyte leukemia (NK-LGLL) is a rare leukemia with CD3-CD16+CD56+ NK cell clonal expansion. The current standard treatments are immunosuppressant therapies, which are not curative. The Janus kinase (JAK) – signal transducer and activator of transcription (STAT) pathway is hyperactivated in LGLL and is one pathway of interest in new drug target investigations. We previously demonstrated the ability of calcitriol to decrease STAT1 tyrosine 701 (p-STAT1) and STAT3 tyrosine 705 (p-STAT3) phosphorylation as well as inflammatory cytokine output of T cell large granular lymphocyte leukemia cells, but did not determine the effects of calcitriol on NK-LGLL. Therefore, in the present study, we investigated whether NKL cells, a model of NK-LGLL, and NK-LGLL patient peripheral blood mononuclear cells (PBMCs) are susceptible to treatment with calcitriol or seocalcitol (EB1089), a potent analog of calcitriol. NKL cells are dependent on interleukin (IL)-2 for survival and we show here for the first time that treatment with IL-2 induced tyrosine phosphorylation of STATs 1 through 6. Both calcitriol and EB1089 caused significant upregulation of the vitamin D receptor (VDR). IL-2 induction of p-STAT1 and p-STAT3 phosphorylation was significantly decreased after calcitriol or EB1089 treatment. Additionally, IL-10, interferon (IFN)-γ, and FMS-like tyrosine kinase 3 ligand (Flt-3L) extracellular output was significantly decreased at 100 nM EB1089 and intracellular IL-10 was decreased with either calcitriol or EB1089 treatment. We treated NK-LGLL patient PBMCs with calcitriol or EB1089 and found decreased p-STAT1 and p-STAT3 while VDR increased, which matched the NKL cell line data. We then measured 75 serum cytokines in NK-LGLL patients (n=8) vs. age- and sex-matched normal healthy donors (n=8), which is the first serum cytokine study for this LGLL subtype. We identified 15 cytokines, including IL-10 and Flt-3L, which were significantly different between normal donors and NK-LGLL patients. Overall, our results suggest that activating the vitamin D pathway could be a mechanism to decrease STAT1 and 3 activation and inflammatory cytokine output in NKLGLL patients.

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“…Vitamin D deficiency was also associated with a decrease in total survival and/or PFS for acute myeloid leukemia, CLL and NHL (24)(25)(26). In a study with 34,763 women with a median age of 63 years, moderate calcium replacement was shown to prevent lymphoid malignancies in elderly women (27). In our patient group, we could not find a relationship between complications, such as thrombosis, haemorrhage, erythrocytosis, thrombocytosis, leukocytosis, and vitamin D deficiency, but the number of patients was insufficient to make a solid conclusion.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D Deficiency and Janus kinase 2 V617F Mutation Status in Essential Thrombocythemia and Polycythemia Vera

Yıkılmaz¹,

Akıncı²,

Bakanay³

et al. 2020

MJMS

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Introduction: Vitamin D, which is known for its effects on calcium and bone metabolism, has recently been associated with haematological malignancies. We aimed to investigate the relationship between disease findings and vitamin D deficiency in essential thrombocythemia (ET) and polycythemia vera (PV).Material and Methods: This retrospective cohort study conducted in Turkey included 73 patients diagnosed with PV or ET according to WHO criteria between 2012 and 2018. Vitamin D deficiency was defined as 25-OH vitamin D < 20 ng/mL. Polymerase chain reaction (PCR) was used to detect the Janus kinase 2 (JAK2) V617F mutation.Results: Vitamin D deficiency was found in 66.7% of PV and 74.2% of ET patients. The median follow-up time of ET and PV patients was 48 months and 47 months, respectively. Patients with the JAK2 mutation had a higher prevalence of a history of thrombosis and age older than 65 years. There was a significant relationship between JAK2 positivity and vitamin D deficiency.Conclusion: There was a remarkably higher prevalence of vitamin D deficiency in JAK2 mutation-positive ET and PV patients. These patients should be carefully evaluated for vitamin D deficiency. More studies are required to further investigate the association between JAK2 and vitamin D.

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Vitamin D in hematological disorders and malignancies

Cited by 69 publications

References 82 publications

The Association between Iron and Vitamin D Status in Female Elite Athletes

The Association between Iron and Vitamin D Status in Female Elite Athletes

Vitamin D pathway activation selectively deactivates signal transducer and activator of transcription (STAT) proteins and inflammatory cytokine production in natural killer leukemic large granular lymphocytes

Vitamin D Deficiency and Janus kinase 2 V617F Mutation Status in Essential Thrombocythemia and Polycythemia Vera

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