1. Helicase-like transcription factor is a RUNX1 target whose downregulation promotes genomic instability and correlates with complex cytogenetic features in acute myeloid leukemia.
- Author
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Cheng CK, Chan NP, Wan TS, Lam LY, Cheung CH, Wong TH, Ip RK, Wong RS, and Ng MH
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antigens, CD34 genetics, Antigens, CD34 metabolism, Binding Sites, Bone Marrow Cells pathology, CCAAT-Enhancer-Binding Proteins genetics, CCAAT-Enhancer-Binding Proteins metabolism, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Proliferation, Chromosome Aberrations, Core Binding Factor Alpha 2 Subunit metabolism, DNA Methylation, DNA-Binding Proteins antagonists & inhibitors, DNA-Binding Proteins metabolism, Female, Genomic Instability, Hematopoiesis genetics, Humans, Karyotype, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Mutation, Promoter Regions, Genetic, Protein Binding, RNA, Messenger antagonists & inhibitors, RNA, Messenger metabolism, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Signal Transduction, Survival Analysis, Transcription Factors antagonists & inhibitors, Transcription Factors metabolism, Bone Marrow Cells metabolism, Core Binding Factor Alpha 2 Subunit genetics, DNA-Binding Proteins genetics, Gene Expression Regulation, Leukemic, Leukemia, Myeloid, Acute genetics, RNA, Messenger genetics, Transcription Factors genetics
- Abstract
Helicase-like transcription factor is a SWI/SNF chromatin remodeling factor involved in various biological processes. However, little is known about its role in hematopoiesis. In this study, we measured helicase-like transcription factor mRNA expression in the bone marrow of 204 adult patients with de novo acute myeloid leukemia. Patients were dichotomized into low and high expression groups at the median level for clinicopathological correlations. Helicase-like transcription factor levels were dramatically reduced in the low expression patient group compared to those in the normal controls (n=40) (P<0.0001). Low helicase-like transcription factor expression correlated positively with French-American-British M4/M5 subtypes (P<0.0001) and complex cytogenetic abnormalities (P=0.02 for ≥3 abnormalities;P=0.004 for ≥5 abnormalities) but negatively with CEBPA double mutations (P=0.012). Also, low expression correlated with poorer overall (P=0.005) and event-free (P=0.006) survival in the intermediate-risk cytogenetic subgroup. Consistent with the more aggressive disease associated with low expression, helicase-like transcription factor knockdown in leukemic cells promoted proliferation and chromosomal instability that was accompanied by downregulation of mitotic regulators and impaired DNA damage response. The significance of helicase-like transcription factor in genome maintenance was further indicated by its markedly elevated expression in normal human CD34(+)hematopoietic stem cells. We further demonstrated that helicase-like transcription factor was a RUNX1 target and transcriptionally repressed by RUNX1-ETO and site-specific DNA methylation through a duplicated RUNX1 binding site in its promoter. Taken together, our findings provide new mechanistic insights on genomic instability linked to helicase-like transcription factor deregulation, and strongly suggest a tumor suppressor function of the SWI/SNF protein in acute myeloid leukemia., (Copyright© Ferrata Storti Foundation.)
- Published
- 2016
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