A Pilot Clinical Study to Investigate the Hypomethylating Properties of Freeze-dried Black Raspberries in Patients with Myelodysplastic Syndrome or Myeloproliferative Neoplasm

Abstract

Myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are bone marrow disorders characterized by cytopenias and progression to acute myeloid leukemia. Hypomethylating agents (HMAs) are Food and Drug Administration-approved therapies for MDS and MDS/MPN patients. HMAs have improved patients' survival and quality of life when compared with other therapies. Although HMAs are effective in MDS and MDS/MPN patients, they are associated with significant toxicities that place a large burden on patients. Our goal is to develop a safer and more effective HMA from natural products. We previously reported that black raspberries (BRBs) have hypomethylating effects in the colon, blood, spleen, and bone marrow of mice. In addition, BRBs exert hypomethylating effects in patients with colorectal cancer and familial adenomatous polyposis. In the current study, we conducted a pilot clinical trial to evaluate the hypomethylating effects of BRBs in patients with low-risk MDS or MDS/MPN. Peripheral blood mononuclear cells (PBMCs) were isolated before and after three months of BRB intervention. CD45 + cells were isolated from PBMCs for methylation analysis using a reduced-representation bisulfite sequencing assay. Each patient served as their own matched control, with their measurements assessed before intervention providing a baseline for post-intervention results. Clinically, our data showed that BRBs were well-tolerated with no side effects. When methylation data was combined, BRBs significantly affected methylation levels of 477 promoter regions. Pathway analysis suggests that BRB-induced intragenic hypomethylation drives leukocyte differentiation. A randomized, placebo-controlled clinical trial of BRB use in low-risk MDS or MDS/ MPN patients is warranted.

Effects of Black Raspberry Supplementation on Methylation Pathways in Vav-cre Asxl1fl/fl Tet2fl/fl Double Knockout Mice with Early-stage Myelodysplastic Syndrome

“…This study demonstrated that the supplementation of diet with 5% BRBs in Vav-cre Asxl1 fl/fl Tet2 fl/fl mice has distinct effects on hematopoietic pathways potentially related to the development of MDS. Our pilot clinical study illustrated the hypomethylating effects of BRBs in individuals diagnosed with myelodysplastic syndrome or myeloproliferative neoplasm [ 8 ]. Pathway analysis indicates that the intragenic hypomethylation induced by BRBs plays a role in prompting leukocyte differentiation.…”

“…4 TSS and intragenic_hyper-and hypo-methylation old wild-type (n = 6) and Vav-cre Asxl1 fl/fl Tet2 fl/fl (n = 10) mice were fed 5% BRBs for 12 weeks. The circulating blood was used for the Wright-Giemsa stain, and CD45 + cells from circulating blood were used for the Reduced Representation Bisulfite Sequencing (RRBS) assay; data analysis was performed as described [8]. A modified software based on Metilene and Wilcoxon Signed Rank Test was applied to identify the differentially methylated region (DMR) de novo among samples.…”

Berries vs. Disease: Revenge of the Phytochemicals

“…These observations were attributed to both a hypomethylation of intergenic regions and a hypermethylation of intragenic and intergenic regions. These effects also manifested without significant side effects or adverse effects in study patients which demonstrates the desired safety profile of BRB intervention [ 97 ]. The precise impact of the observed hypermethylation events will require further investigation.…”

Bioinformatics gene analysis of potential biomarkers and therapeutic targets of osteoarthritis associated myelodysplastic syndrome

“…Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal diseases originating from hematopoietic myeloid-directed stem cells or pluripotent stem cells, and about 10% of patients with MDS may develop secondary to autoimmune diseases ( Dong et al, 2022 ). It has been shown that some patients with MDS have a higher probability of secondary autoimmune disease than their natural incidence, while others have no clinical manifestations of immune disease but may have abnormal immunologic parameters, providing further evidence of the association between MDS and autoimmune disease ( Wang et al, 2022 ).…”