A Pilot Clinical Study to Investigate the Hypomethylating Properties of Freeze-dried Black Raspberries in Patients with Myelodysplastic Syndrome or Myeloproliferative Neoplasm.
A Pilot Clinical Study to Investigate the Hypomethylating Properties of Freeze-dried Black Raspberries in Patients with Myelodysplastic Syndrome or Myeloproliferative Neoplasm.
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DOI：
10.15430/jcp.2022.27.2.129
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发表时间：
2022-06-30
影响因子：
2.5
通讯作者：
Atallah, Ehab
中科院分区：
文献类型：
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作者：
Dong, Athena;Pan, Xiaoqing;Lin, Chien-Wei;Huang, Yi-Wen;Krause, Hayden;Pan, Pan;Baim, Arielle;Thomas, Michael J.;Chen, Xiao;Yu, Jianhua;Michaelis, Laura;Liu, Pengyuan;Wang, Li-Shu;Atallah, Ehab
关键词：
骨髓增生异常综合征（MDS）和骨髓增生异常/骨髓增生性肿瘤（MDS/MPN）是以血细胞减少和进展为急性髓性白血病为特征的骨髓疾病。低甲基化剂（HMA）是食品和药物管理局批准的用于MDS和MDS/MPN患者的疗法。与其他疗法相比，HMA改善了患者的生存率和生活质量。虽然HMA在MDS和MDS/MPN患者中有效，但它们与给患者带来巨大负担的显著毒性相关。我们的目标是从天然产品中开发更安全，更有效的HMA。我们以前报道过，黑树莓（BRB）在小鼠的结肠，血液，脾脏和骨髓中具有低甲基化作用。此外，BRB在结直肠癌和家族性腺瘤性息肉病患者中发挥低甲基化作用。在目前的研究中，我们进行了一项初步临床试验，以评估BRB在低危MDS或MDS/MPN患者中的低甲基化作用。在BRB干预三个月之前和之后分离外周血单核细胞（PBMCs）。从PBMC中分离CD 45+细胞，用于使用简化代表性亚硫酸氢盐测序测定进行甲基化分析。每个患者都作为自己的匹配对照，在干预前评估他们的测量值，为干预后的结果提供基线。临床上，我们的数据显示BRB耐受性良好，无副作用。当结合甲基化数据时，BRB显著影响477个启动子区域的甲基化水平。通路分析表明，BRB诱导的基因内低甲基化驱动白细胞分化。在低风险MDS或MDS/MPN患者中进行BRB使用的随机、安慰剂对照临床试验是必要的。
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.