Histone deacetylase inhibitors induce leukemia gene expression in cord blood hematopoietic stem cells expanded ex vivo

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• 作者：Yuk Man Lam ; Yuen Fan Chan ; Li Chong Chan…
• 关键词：Hematopoietic stem cell ; Ex vivo expansion ; Cord blood ; Histone deacetylase inhibitor
• 刊名：International Journal of Hematology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：105
• 期：1
• 页码：37-43
• 全文大小：
• 刊物主题：Hematology; Oncology;
• 出版者：Springer Japan
• ISSN：1865-3774
• 卷排序：105

文摘

Umbilical cord blood is a valuable source of hematopoietic stem cells. While cytokine stimulation can induce ex vivo hematopoietic cell proliferation, attempts have been made to use epigenetic-modifying agents to facilitate stem cell expansion through the modulation of cellular epigenetic status. However, the potential global effect of these modifying agents on epigenome raises concerns about the functional normality of the expanded cells. We studied the ex vivo expansion of cord blood hematopoietic stem and progenitor cells (HSPCs) by histone deacetylase (HDAC) inhibitors, trichostatin A and valproic acid. Treatment with HDAC inhibitors resulted in mild expansion of the total hematopoietic cell number when compared with cytokine stimulated sample. Nevertheless, we observed 20–30-fold expansion of the CD34+ CD38− HSPC population. Strikingly, cord blood cells cultured with HDAC inhibitors exhibited aberrant expression of leukemia-associated genes, including CDKN1C, CEBPα, HOXA9, MN1, and DLK1. Our results thus suggest that the expansion of HSPCs by this approach may provoke a pre-leukemic cell state. We propose that the alteration of epigenome by HDAC inhibitors readily expands cord blood HSPC population through the re-activation of the leukemia gene transcription. The present study provides an assessment of the leukemogenic potential of HSCs expanded ex vivo using HDAC inhibitors for clinical applications.