Detection of Pathogenic Isoforms of IKZF1 in Leukemic Cell Lines and Acute Lymphoblastic Leukemia Samples: Identification of a Novel Truncated IKZF1 Transcript in SUP-B15.
Simple Summary: Abnormal RNA splicing plays a fundamental role in leukemogenesis in acute lymphoblastic leukemia (ALL). Many cases of high-risk B-cell ALL cases, including BCR-ABL1+ and BCR-ABL1-like ALL, share a common molecular mechanism of aberrant fusion transcripts involving tyrosine kinase gen...
| Publicado en: | Cancers Vol. 12; no. 11; pp. 3161 - 3162 |
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| Autores principales: | , , , , , , , , , |
| Formato: | pictorial research tables/charts Journal Article |
| Publicado: |
MDPI
Nov2020
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=147285172&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 147285172 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 20726694 B74B jtl: Cancers issn: 20726694 maglogo: N pubinfo: dt: Nov2020 vid: 12 iid: 11 pid: 97109 pub: MDPI artinfo: ui: 147285172 147285172 147285172 10.3390/cancers12113161 147285172 ppf: 3161 ppct: 1 formats: tig: atl: Detection of Pathogenic Isoforms of IKZF1 in Leukemic Cell Lines and Acute Lymphoblastic Leukemia Samples: Identification of a Novel Truncated IKZF1 Transcript in SUP-B15. aug: au: Zhao, Weiqiang Li, Ying Yao, Chenjiao Zhang, Guojuan Zhao, Kevin Y. Chen, Wei Ru, Peng Pan, Xiaokang Tu, Huolin Jones, Daniel affil: The James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA sug: subj: Leukemia, Lymphocytic, Acute Physiopathology Leukemia, Lymphocytic, Acute Prognosis Cell Line, Tumor Analysis Neoplastic Processes RNA Mutation Transcription Factors Human Adult Oncogenes Protein-Tyrosine Kinases Genetic Techniques Interleukins Gene Expression Profiling Histone Deacetylases Antagonists and Inhibitors Age Factors Chromosome Aberrations Adult: 19-44 years ab: Simple Summary: Abnormal RNA splicing plays a fundamental role in leukemogenesis in acute lymphoblastic leukemia (ALL). Many cases of high-risk B-cell ALL cases, including BCR-ABL1+ and BCR-ABL1-like ALL, share a common molecular mechanism of aberrant fusion transcripts involving tyrosine kinase genes combined with dysregulation of the transcription factor and lymphocyte differentiation factor IKZF1. Dysfunction of IKZF1 in ALL is caused by mutation and gene deletion but also alternative splicing resulting in exon skipping with production of aberrant IKZF1 proteins. We report here an assay to detect aberrantly spliced isoforms of IKZF1 in ALL to assist in diagnosis, outcome prediction, and therapy selection in ALL and the identification of a novel altered IKZF1 product in a model ALL cell line. Leukemia-associated alternative splicing of IKZF1 can result in proteins with loss of one to four copies of its N-terminal zinc finger domains (N-ZnF). The best characterized pathogenic splice isoforms, Ik-6 and Ik-8, have been commonly found in BCR-ABL1+ acute lymphoblastic leukemia (ALL) and a subset of BCR-ABL1-like ALL. Infantile and childhood ALL that express these pathogenic IKZF1 isoforms have shown inferior clinical outcomes and can be resistant to tyrosine kinase inhibitors. Using ALL cell lines, we designed and validated a method to detect abnormal IKZF1 transcripts. In the SUP-B15 leukemia cell line, we noted novel IKZF1 transcripts that include both an Ik-6 splice and a transcript with a 14 base pair insertion at the C-terminus. There was also increased IKZF2 protein in SUP-B15 as compared to other ALL lines. Expression of Ik-6 could be suppressed by treatment with the pro-apoptotic type II histone deacetylase inhibitor givinostat. In 17 adult ALL samples, we noted the Ik-6 isoforms in 6 of 15 BCR-ABL1−, and 1 of 2 BCR-ABL1+ cases, with Ik-8 also expressed in one case. Cases with Ik-6 expression showed inferior survival as well as older age at presentation, lower expression of CD10 and more commonly a diploid karyotype. pubtype: Academic Journal doctype: pictorial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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