Detection of Pathogenic Isoforms of <em>IKZF1</em> in Leukemic Cell Lines and Acute Lymphoblastic Leukemia Samples: Identification of a Novel Truncated IKZF1 Transcript in SUP-B15
Leukemia-associated alternative splicing of <i>IKZF1</i> 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 leuke...
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MDPI AG
2020-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/11/3161 |
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| author | Weiqiang Zhao Ying Li Chenjiao Yao Guojuan Zhang Kevin Y. Zhao Wei Chen Peng Ru Xiaokang Pan Huolin Tu Daniel Jones |
| author_facet | Weiqiang Zhao Ying Li Chenjiao Yao Guojuan Zhang Kevin Y. Zhao Wei Chen Peng Ru Xiaokang Pan Huolin Tu Daniel Jones |
| author_sort | Weiqiang Zhao |
| collection | DOAJ |
| description | Leukemia-associated alternative splicing of <i>IKZF1</i> 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 <i>IKZF1</i> transcripts. In the SUP-B15 leukemia cell line, we noted novel <i>IKZF1</i> 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<sup>−</sup>, and 1 of 2 BCR-ABL1<sup>+</sup> 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. |
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| spelling | doaj.art-3f031fac508b419fa5c5659944b125552023-11-20T18:47:39ZengMDPI AGCancers2072-66942020-10-011211316110.3390/cancers12113161Detection of Pathogenic Isoforms of <em>IKZF1</em> in Leukemic Cell Lines and Acute Lymphoblastic Leukemia Samples: Identification of a Novel Truncated IKZF1 Transcript in SUP-B15Weiqiang Zhao0Ying Li1Chenjiao Yao2Guojuan Zhang3Kevin Y. Zhao4Wei Chen5Peng Ru6Xiaokang Pan7Huolin Tu8Daniel Jones9The James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USAThe Department of Pediatrics and Department of Hematology, Xiang-Ya Third Hospital, Changsha 410013, ChinaThe Department of Pediatrics and Department of Hematology, Xiang-Ya Third Hospital, Changsha 410013, ChinaThe James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USAThe James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USAThe James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USAThe James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USAThe James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USAThe James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USAThe James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USALeukemia-associated alternative splicing of <i>IKZF1</i> 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 <i>IKZF1</i> transcripts. In the SUP-B15 leukemia cell line, we noted novel <i>IKZF1</i> 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<sup>−</sup>, and 1 of 2 BCR-ABL1<sup>+</sup> 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.https://www.mdpi.com/2072-6694/12/11/3161ALLIKZF1isoformssurvivalIk-6Ik-8 |
| spellingShingle | Weiqiang Zhao Ying Li Chenjiao Yao Guojuan Zhang Kevin Y. Zhao Wei Chen Peng Ru Xiaokang Pan Huolin Tu Daniel Jones Detection of Pathogenic Isoforms of <em>IKZF1</em> in Leukemic Cell Lines and Acute Lymphoblastic Leukemia Samples: Identification of a Novel Truncated IKZF1 Transcript in SUP-B15 Cancers ALL IKZF1 isoforms survival Ik-6 Ik-8 |
| title | Detection of Pathogenic Isoforms of <em>IKZF1</em> in Leukemic Cell Lines and Acute Lymphoblastic Leukemia Samples: Identification of a Novel Truncated IKZF1 Transcript in SUP-B15 |
| title_full | Detection of Pathogenic Isoforms of <em>IKZF1</em> in Leukemic Cell Lines and Acute Lymphoblastic Leukemia Samples: Identification of a Novel Truncated IKZF1 Transcript in SUP-B15 |
| title_fullStr | Detection of Pathogenic Isoforms of <em>IKZF1</em> in Leukemic Cell Lines and Acute Lymphoblastic Leukemia Samples: Identification of a Novel Truncated IKZF1 Transcript in SUP-B15 |
| title_full_unstemmed | Detection of Pathogenic Isoforms of <em>IKZF1</em> in Leukemic Cell Lines and Acute Lymphoblastic Leukemia Samples: Identification of a Novel Truncated IKZF1 Transcript in SUP-B15 |
| title_short | Detection of Pathogenic Isoforms of <em>IKZF1</em> in Leukemic Cell Lines and Acute Lymphoblastic Leukemia Samples: Identification of a Novel Truncated IKZF1 Transcript in SUP-B15 |
| title_sort | detection of pathogenic isoforms of em ikzf1 em in leukemic cell lines and acute lymphoblastic leukemia samples identification of a novel truncated ikzf1 transcript in sup b15 |
| topic | ALL IKZF1 isoforms survival Ik-6 Ik-8 |
| url | https://www.mdpi.com/2072-6694/12/11/3161 |
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