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Regulation of Cellular Proliferation in B‐cell Acute Lymphoblastic Leukemia by Ikaros
Author(s) -
Dovat Elanora,
Payne Jonathon L,
Song Chunhua,
Desai Dhimant
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.756.17
Subject(s) - biology , transcription factor , pi3k/akt/mtor pathway , repressor , epigenetics , promoter , cell cycle , cell growth , psychological repression , cancer research , microbiology and biotechnology , gene , genetics , signal transduction , gene expression
B‐cell acute lymphoblastic leukemia (B‐ALL) is the most common malignancy of childhood. IKZF1 encodes the Ikaros protein that acts as a tumor suppressor in B‐ALL. In high‐risk B‐ALL that is characterized by poor prognosis, the activity of Ikaros as a tumor suppressor is impaired. The goal of our research is to define the mechanisms through which Ikaros regulates cellular proliferation in high‐risk B‐ALL. In gain‐of‐function experiments, we overexpressed Ikaros in B‐ALL cells via retroviral transduction. Ikaros overexpression results in transcriptional repression of a large set of genes that promote cell cycle progression and several genes that promote the Phosphoinositide 3‐kinase (PI3K) pathway. This was associated with increased Ikaros binding at promoters of these genes. Ikaros loss‐of‐function experiments in which Ikaros in B‐ALL was downregulated by transfection with a specific Ikaros shRNA, resulted in increased transcription of Ikaros target genes. These results suggest that Ikaros can regulate the cell cycle and PI3K pathway in B‐ALL by functioning as a transcriptional repressor of the genes that promote cell cycle progression and the PI3K pathway. Since both cell cycle control and the PI3K pathway are dysregulated in high‐risk B‐ALL, these data provide a mechanism for how impaired Ikaros function results in the development of high‐risk B‐ALL. To determine the mechanism trough which Ikaros represses transcription of genes that regulate cellular proliferation in B‐ALL, we performed fine mapping of Ikaros binding and identified the epigenetic signature of the promoters of Ikaros target genes in B‐ALL cells using serial quantitative chromatin immunoprecipitation (qChIP). Results showed that Ikaros binding to the promoters of its target genes is associated with the formation of repressive chromatin that is characterized by the presence of specific histone modifications – H3K27me3 or H3K9me3. These data suggest that Ikaros represses the transcription of genes that regulate cellular proliferation via chromatin remodeling. In summary, the presented data demonstrate that Ikaros controls cellular proliferation in B‐ALL by direct transcriptional repression of genes that promote cell cycle progression and the PI3K pathway via epigenetic mechanisms. The loss of Ikaros function results in the deregulation of cell cycle control and the PI3K pathway and the development of high‐risk B‐ALL. Results provide the groundwork for further studies of the epigenetic regulation of gene expression in B‐ALL. Support or Funding Information Supported by St. Baldrick's Foundation Summer Fellowship (E.D.)