<i>NELL2</i>-<i>PAX7</i> Transcriptional Cascade Suggests Activation Mechanism for <i>RAD52</i>-Dependent Alternative Lengthening of Telomeres During Malignant Transformation of Malignant Peripheral Nerve Sheath Tumors: Elongation of Telomeres and Poor Survival
<b>Background</b>: In eukaryotes with a double-stranded linear DNA genome, the loss of terminal DNA during replication is inevitable due to an end-replication problem; here, telomeres serve as a buffer against DNA loss. Thus, the activation of the telomere maintenance mechanism (TMM) is...
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2025-01-01
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| author | Jungwoo Lee Eunji Choi Hyoju Kim Young-Joon Kim Seung Hyun Kim |
| author_facet | Jungwoo Lee Eunji Choi Hyoju Kim Young-Joon Kim Seung Hyun Kim |
| author_sort | Jungwoo Lee |
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| description | <b>Background</b>: In eukaryotes with a double-stranded linear DNA genome, the loss of terminal DNA during replication is inevitable due to an end-replication problem; here, telomeres serve as a buffer against DNA loss. Thus, the activation of the telomere maintenance mechanism (TMM) is a prerequisite for malignant transformation. <b>Methods</b>: We compared neurofibroma (NF, benign) and malignant peripheral nerve sheath tumors (MPNSTs) occurring in the same patient with type 1 neurofibromatosis, where each NF–MPNST pair shared the same genetic background and differentiation lineage; this minimizes the genetic bias and contrasts only those changes that are related to malignant transformation. A total of 20 NF–MPNST pairs from 20 NF1 patients were analyzed. Whole-transcriptome sequencing (WTS) was conducted to profile the transcriptional relationship, and whole-genome sequencing (WGS) was performed to measure the telomere length. <b>Results</b>: We identified 22 differentially expressed genes (DEGs) during the malignant transformation of MPNSTs. Among them, <i>NELL2</i> activated <i>PAX7</i>, which sequentially activated <i>RAD52</i>, the recombinase of RAD52-dependent alternative lengthening of telomeres (ALT). <i>RAD52</i> elongated MPNSTs–telomeres (<i>p</i> = 0.017). Otherwise, neither <i>NELL2</i> nor <i>PAX7</i> affected telomere length (<i>p</i> = 0.647 and <i>p</i> = 0.354, respectively). <i>RAD52</i> increased MPNSTs–telomeres length, independently of <i>NELL2</i> and <i>PAX7</i> in multiple analyses (<i>p</i> = 0.021). The group with increased telomere length during the malignant transformation showed inferior overall survival (OS) (HR = 3.809, <i>p</i> = 0.038) to the group without increased telomere length. Accordingly, the group with increased <i>PAX7</i> showed inferior OS (HR = 4.896, <i>p</i> = 0.046) and metastasis-free survival (MFS) (HR = 9.129, <i>p</i> = 0.007) in comparison to the group without increased <i>PAX7</i>; the group with increased <i>RAD52</i> showed inferior MFS (HR = 8.669, <i>p</i> = 0.011) in comparison to the group without increased <i>RAD52</i>. <b>Conclusions</b>: We suggest that the <i>NELL2</i>-<i>PAX7</i> transcriptional cascade activates RAD52-dependent ALT to increase telomere length during the malignant transformation of MPNSTs, resulting in a poor prognosis. |
| format | Article |
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| spelling | doaj-art-95f626714b9c487eb96a429c6a67d0eb2025-08-20T02:44:34ZengMDPI AGBiomedicines2227-90592025-01-0113228110.3390/biomedicines13020281<i>NELL2</i>-<i>PAX7</i> Transcriptional Cascade Suggests Activation Mechanism for <i>RAD52</i>-Dependent Alternative Lengthening of Telomeres During Malignant Transformation of Malignant Peripheral Nerve Sheath Tumors: Elongation of Telomeres and Poor SurvivalJungwoo Lee0Eunji Choi1Hyoju Kim2Young-Joon Kim3Seung Hyun Kim4Interdisciplinary Program of Integrated OMICS for Biomedical Science, The Graduate School, Yonsei University, Seoul 03722, Republic of KoreaInterdisciplinary Program of Integrated OMICS for Biomedical Science, The Graduate School, Yonsei University, Seoul 03722, Republic of KoreaInterdisciplinary Program of Integrated OMICS for Biomedical Science, The Graduate School, Yonsei University, Seoul 03722, Republic of KoreaInterdisciplinary Program of Integrated OMICS for Biomedical Science, The Graduate School, Yonsei University, Seoul 03722, Republic of KoreaDepartment of Orthopaedic Surgery, Yonsei University College of Medicine, 50-1, Yonsei-Ro, Seodaemun-gu, Seoul 03722, Republic of Korea<b>Background</b>: In eukaryotes with a double-stranded linear DNA genome, the loss of terminal DNA during replication is inevitable due to an end-replication problem; here, telomeres serve as a buffer against DNA loss. Thus, the activation of the telomere maintenance mechanism (TMM) is a prerequisite for malignant transformation. <b>Methods</b>: We compared neurofibroma (NF, benign) and malignant peripheral nerve sheath tumors (MPNSTs) occurring in the same patient with type 1 neurofibromatosis, where each NF–MPNST pair shared the same genetic background and differentiation lineage; this minimizes the genetic bias and contrasts only those changes that are related to malignant transformation. A total of 20 NF–MPNST pairs from 20 NF1 patients were analyzed. Whole-transcriptome sequencing (WTS) was conducted to profile the transcriptional relationship, and whole-genome sequencing (WGS) was performed to measure the telomere length. <b>Results</b>: We identified 22 differentially expressed genes (DEGs) during the malignant transformation of MPNSTs. Among them, <i>NELL2</i> activated <i>PAX7</i>, which sequentially activated <i>RAD52</i>, the recombinase of RAD52-dependent alternative lengthening of telomeres (ALT). <i>RAD52</i> elongated MPNSTs–telomeres (<i>p</i> = 0.017). Otherwise, neither <i>NELL2</i> nor <i>PAX7</i> affected telomere length (<i>p</i> = 0.647 and <i>p</i> = 0.354, respectively). <i>RAD52</i> increased MPNSTs–telomeres length, independently of <i>NELL2</i> and <i>PAX7</i> in multiple analyses (<i>p</i> = 0.021). The group with increased telomere length during the malignant transformation showed inferior overall survival (OS) (HR = 3.809, <i>p</i> = 0.038) to the group without increased telomere length. Accordingly, the group with increased <i>PAX7</i> showed inferior OS (HR = 4.896, <i>p</i> = 0.046) and metastasis-free survival (MFS) (HR = 9.129, <i>p</i> = 0.007) in comparison to the group without increased <i>PAX7</i>; the group with increased <i>RAD52</i> showed inferior MFS (HR = 8.669, <i>p</i> = 0.011) in comparison to the group without increased <i>RAD52</i>. <b>Conclusions</b>: We suggest that the <i>NELL2</i>-<i>PAX7</i> transcriptional cascade activates RAD52-dependent ALT to increase telomere length during the malignant transformation of MPNSTs, resulting in a poor prognosis.https://www.mdpi.com/2227-9059/13/2/281telomere<i>NELL2</i><i>PAX7</i>RAD52-dependent ALTMPNST |
| spellingShingle | Jungwoo Lee Eunji Choi Hyoju Kim Young-Joon Kim Seung Hyun Kim <i>NELL2</i>-<i>PAX7</i> Transcriptional Cascade Suggests Activation Mechanism for <i>RAD52</i>-Dependent Alternative Lengthening of Telomeres During Malignant Transformation of Malignant Peripheral Nerve Sheath Tumors: Elongation of Telomeres and Poor Survival Biomedicines telomere <i>NELL2</i> <i>PAX7</i> RAD52-dependent ALT MPNST |
| title | <i>NELL2</i>-<i>PAX7</i> Transcriptional Cascade Suggests Activation Mechanism for <i>RAD52</i>-Dependent Alternative Lengthening of Telomeres During Malignant Transformation of Malignant Peripheral Nerve Sheath Tumors: Elongation of Telomeres and Poor Survival |
| title_full | <i>NELL2</i>-<i>PAX7</i> Transcriptional Cascade Suggests Activation Mechanism for <i>RAD52</i>-Dependent Alternative Lengthening of Telomeres During Malignant Transformation of Malignant Peripheral Nerve Sheath Tumors: Elongation of Telomeres and Poor Survival |
| title_fullStr | <i>NELL2</i>-<i>PAX7</i> Transcriptional Cascade Suggests Activation Mechanism for <i>RAD52</i>-Dependent Alternative Lengthening of Telomeres During Malignant Transformation of Malignant Peripheral Nerve Sheath Tumors: Elongation of Telomeres and Poor Survival |
| title_full_unstemmed | <i>NELL2</i>-<i>PAX7</i> Transcriptional Cascade Suggests Activation Mechanism for <i>RAD52</i>-Dependent Alternative Lengthening of Telomeres During Malignant Transformation of Malignant Peripheral Nerve Sheath Tumors: Elongation of Telomeres and Poor Survival |
| title_short | <i>NELL2</i>-<i>PAX7</i> Transcriptional Cascade Suggests Activation Mechanism for <i>RAD52</i>-Dependent Alternative Lengthening of Telomeres During Malignant Transformation of Malignant Peripheral Nerve Sheath Tumors: Elongation of Telomeres and Poor Survival |
| title_sort | i nell2 i i pax7 i transcriptional cascade suggests activation mechanism for i rad52 i dependent alternative lengthening of telomeres during malignant transformation of malignant peripheral nerve sheath tumors elongation of telomeres and poor survival |
| topic | telomere <i>NELL2</i> <i>PAX7</i> RAD52-dependent ALT MPNST |
| url | https://www.mdpi.com/2227-9059/13/2/281 |
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