title: Histone deacetylase inhibitors induce leukemia gene expression in cord blood hematopoietic stem cells expanded ex vivo.
abstract: 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.
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Yuk Man
authors.initials: YM
authors.lastname: Lam
authors.affiliation: Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Yuen Fan
authors.initials: YF
authors.lastname: Chan
authors.affiliation: Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.|Centre for Reproduction, Development and Growth, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Li Chong
authors.initials: LC
authors.lastname: Chan
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. raykitng@hku.hk.|Centre for Reproduction, Development and Growth, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. raykitng@hku.hk.|Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. raykitng@hku.hk.
authors.forename: Ray Kit
authors.initials: RK
authors.lastname: Ng
mesh_terms: D018929:Cell Culture Techniques; D002478:Cells, Cultured; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects* / Q000494:pharmacology; D007938:Leukemia / Q000139:chemically induced* / Q000235:genetics*; D014635:Valproic Acid / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D014635:Valproic Acid
keywords: Cord blood; Ex vivo expansion; Hematopoietic stem cell; Histone deacetylase inhibitor