Malignant DFFB isoform switching promotes leukemia survival in relapse pediatric T‐cell acute lymphoblastic leukemia
Abstract With modern treatment most children with acute lymphoblastic leukemia (ALL) survive without relapse. However, for children who relapse the prognosis is still poor, especially in children with T‐cell phenotype (T‐ALL) and remains the major cause of death. The exact mechanism of relapse is cu...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-02-01
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| Series: | eJHaem |
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| Online Access: | https://doi.org/10.1002/jha2.634 |
| _version_ | 1827318933472935936 |
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| author | Sabina Enlund Indranil Sinha Amanda Ramilo Amor Shahrzad Shirazi Fard Ekaterina Pokrovskaja Tamm Qingfei Jiang Vanessa Lundin Anna Nilsson Frida Holm |
| author_facet | Sabina Enlund Indranil Sinha Amanda Ramilo Amor Shahrzad Shirazi Fard Ekaterina Pokrovskaja Tamm Qingfei Jiang Vanessa Lundin Anna Nilsson Frida Holm |
| author_sort | Sabina Enlund |
| collection | DOAJ |
| description | Abstract With modern treatment most children with acute lymphoblastic leukemia (ALL) survive without relapse. However, for children who relapse the prognosis is still poor, especially in children with T‐cell phenotype (T‐ALL) and remains the major cause of death. The exact mechanism of relapse is currently not known. While contribution of RNA processing alteration has been linked to other hematological malignancies, its contribution in pediatric T‐ALL may provide new insights. Almost all human genes express more than one alternative splice isoform. Thus, gene modulation producing a diverse repertoire of the transcriptome and proteome have become a significant molecular marker of cancer and a potential therapeutic vulnerability. To study this, we performed RNA‐sequencing analysis on patient‐derived samples followed by splice isoform‐specific PCR. We uncovered a distinct RNA splice isoform expression pattern characteristic for relapse samples compared to the leukemia samples from the time of diagnosis. We also identified deregulated splicing and apoptosis pathways specific for relapse T‐ALL. Moreover, patients with T‐ALL displayed pro‐survival splice isoform switching favoring pro‐survival isoforms compared to normal healthy stem cells. Cumulatively, pro‐survival isoform switching and DFFB isoform regulation of SOX2 and MYCN may play a role in T‐ALL proliferation and survival, thus serving as a potential therapeutic option. |
| first_indexed | 2024-03-12T14:06:37Z |
| format | Article |
| id | doaj.art-5deda66b7cfd4c549e5f196698d58ad1 |
| institution | Directory Open Access Journal |
| issn | 2688-6146 |
| language | English |
| last_indexed | 2024-04-25T00:10:06Z |
| publishDate | 2023-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | eJHaem |
| spelling | doaj.art-5deda66b7cfd4c549e5f196698d58ad12024-03-13T13:30:47ZengWileyeJHaem2688-61462023-02-014111512410.1002/jha2.634Malignant DFFB isoform switching promotes leukemia survival in relapse pediatric T‐cell acute lymphoblastic leukemiaSabina Enlund0Indranil Sinha1Amanda Ramilo Amor2Shahrzad Shirazi Fard3Ekaterina Pokrovskaja Tamm4Qingfei Jiang5Vanessa Lundin6Anna Nilsson7Frida Holm8Deparment of Women's and Children's Health Division of Pediatric Oncology and Surgery Karolinska Insitutet Stockholm SwedenDeparment of Women's and Children's Health Division of Pediatric Oncology and Surgery Karolinska Insitutet Stockholm SwedenDeparment of Women's and Children's Health Division of Pediatric Oncology and Surgery Karolinska Insitutet Stockholm SwedenDeparment of Women's and Children's Health Division of Pediatric Oncology and Surgery Karolinska Insitutet Stockholm SwedenDepartment of Oncology‐Pathology Karolinska Institutet Stockholm SwedenDivision of Regenerative Medicine Department of Medicine Sanford Consortium for Regenerative Medicine University of California La Jolla California USACenter for Hematology and Regenerative Medicine Department of Medicine Huddinge Karolinska Institutet Stockholm SwedenDeparment of Women's and Children's Health Division of Pediatric Oncology and Surgery Karolinska Insitutet Stockholm SwedenDeparment of Women's and Children's Health Division of Pediatric Oncology and Surgery Karolinska Insitutet Stockholm SwedenAbstract With modern treatment most children with acute lymphoblastic leukemia (ALL) survive without relapse. However, for children who relapse the prognosis is still poor, especially in children with T‐cell phenotype (T‐ALL) and remains the major cause of death. The exact mechanism of relapse is currently not known. While contribution of RNA processing alteration has been linked to other hematological malignancies, its contribution in pediatric T‐ALL may provide new insights. Almost all human genes express more than one alternative splice isoform. Thus, gene modulation producing a diverse repertoire of the transcriptome and proteome have become a significant molecular marker of cancer and a potential therapeutic vulnerability. To study this, we performed RNA‐sequencing analysis on patient‐derived samples followed by splice isoform‐specific PCR. We uncovered a distinct RNA splice isoform expression pattern characteristic for relapse samples compared to the leukemia samples from the time of diagnosis. We also identified deregulated splicing and apoptosis pathways specific for relapse T‐ALL. Moreover, patients with T‐ALL displayed pro‐survival splice isoform switching favoring pro‐survival isoforms compared to normal healthy stem cells. Cumulatively, pro‐survival isoform switching and DFFB isoform regulation of SOX2 and MYCN may play a role in T‐ALL proliferation and survival, thus serving as a potential therapeutic option.https://doi.org/10.1002/jha2.634acute leukaemiaalternative mRNA splicingapoptosisCD34childhood leukaemiarelapse |
| spellingShingle | Sabina Enlund Indranil Sinha Amanda Ramilo Amor Shahrzad Shirazi Fard Ekaterina Pokrovskaja Tamm Qingfei Jiang Vanessa Lundin Anna Nilsson Frida Holm Malignant DFFB isoform switching promotes leukemia survival in relapse pediatric T‐cell acute lymphoblastic leukemia eJHaem acute leukaemia alternative mRNA splicing apoptosis CD34 childhood leukaemia relapse |
| title | Malignant DFFB isoform switching promotes leukemia survival in relapse pediatric T‐cell acute lymphoblastic leukemia |
| title_full | Malignant DFFB isoform switching promotes leukemia survival in relapse pediatric T‐cell acute lymphoblastic leukemia |
| title_fullStr | Malignant DFFB isoform switching promotes leukemia survival in relapse pediatric T‐cell acute lymphoblastic leukemia |
| title_full_unstemmed | Malignant DFFB isoform switching promotes leukemia survival in relapse pediatric T‐cell acute lymphoblastic leukemia |
| title_short | Malignant DFFB isoform switching promotes leukemia survival in relapse pediatric T‐cell acute lymphoblastic leukemia |
| title_sort | malignant dffb isoform switching promotes leukemia survival in relapse pediatric t cell acute lymphoblastic leukemia |
| topic | acute leukaemia alternative mRNA splicing apoptosis CD34 childhood leukaemia relapse |
| url | https://doi.org/10.1002/jha2.634 |
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