Malignant DFFB isoform switching promotes leukemia survival in relapse pediatric T-cell acute lymphoblastic leukemia.

Autor: Enlund S; Deparment of Women's and Children's Health Division of Pediatric Oncology and Surgery Karolinska Insitutet Stockholm Sweden., Sinha I; Deparment of Women's and Children's Health Division of Pediatric Oncology and Surgery Karolinska Insitutet Stockholm Sweden., Amor AR; Deparment of Women's and Children's Health Division of Pediatric Oncology and Surgery Karolinska Insitutet Stockholm Sweden., Fard SS; Deparment of Women's and Children's Health Division of Pediatric Oncology and Surgery Karolinska Insitutet Stockholm Sweden., Tamm EP; Department of Oncology-Pathology Karolinska Institutet Stockholm Sweden., Jiang Q; Division of Regenerative Medicine Department of Medicine Sanford Consortium for Regenerative Medicine University of California La Jolla California USA.; Moores Cancer Center La Jolla California USA., Lundin V; Center for Hematology and Regenerative Medicine Department of Medicine Huddinge Karolinska Institutet Stockholm Sweden., Nilsson A; Deparment of Women's and Children's Health Division of Pediatric Oncology and Surgery Karolinska Insitutet Stockholm Sweden., Holm F; Deparment of Women's and Children's Health Division of Pediatric Oncology and Surgery Karolinska Insitutet Stockholm Sweden.
Jazyk: angličtina
Zdroj: EJHaem [EJHaem] 2022 Dec 30; Vol. 4 (1), pp. 115-124. Date of Electronic Publication: 2022 Dec 30 (Print Publication: 2023).
DOI: 10.1002/jha2.634
Abstrakt: 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.
Competing Interests: The authors declare no conflict of interest.
(© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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