Tcf-1 promotes genomic instability and T cell transformation in response to aberrant β-catenin activation
Understanding the mechanisms promoting chromosomal translocations of the rearranging receptor loci in leukemia and lymphoma remains incomplete. Here we show that leukemias induced by aberrant activation of β-catenin in thymocytes, which bear recurrent Tcra/Myc-Pvt1 translocations, depend on Tcf-1. The DNA double strand breaks (DSBs) in the Tcra site of the translocation are Rag-generated, whereas the Myc-Pvt1 DSBs are not. Aberrantly activated β-catenin redirects Tcf-1 binding to novel DNA sites to alter chromatin accessibility and down-regulate genome-stability pathways. Impaired homologous recombination (HR) DNA repair and replication checkpoints lead to retention of DSBs that promote translocations and transformation of double-positive (DP) thymocytes. The resulting lymphomas, which resemble human T cell acute lymphoblastic leukemia (T-ALL), are sensitive to PARP inhibitors (PARPis). Our findings indicate that aberrant β-catenin signaling contributes to translocations in thymocytes by guiding Tcf-1 to promote the generation and retention of replication-induced DSBs allowing their coexistence with Rag-generated DSBs. Thus, PARPis could offer therapeutic options in hematologic malignancies with active Wnt/β-catenin signaling.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:119 |
|---|---|
| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 119(2022), 32 vom: 09. Aug., Seite e2201493119 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Arnovitz, Stephen [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 05.08.2022 Date Revised 01.05.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1073/pnas.2201493119 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM344410196 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM344410196 | ||
| 003 | DE-627 | ||
| 005 | 20231226022714.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1073/pnas.2201493119 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1147.xml |
| 035 | |a (DE-627)NLM344410196 | ||
| 035 | |a (NLM)35921443 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Arnovitz, Stephen |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Tcf-1 promotes genomic instability and T cell transformation in response to aberrant β-catenin activation |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 05.08.2022 | ||
| 500 | |a Date Revised 01.05.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Understanding the mechanisms promoting chromosomal translocations of the rearranging receptor loci in leukemia and lymphoma remains incomplete. Here we show that leukemias induced by aberrant activation of β-catenin in thymocytes, which bear recurrent Tcra/Myc-Pvt1 translocations, depend on Tcf-1. The DNA double strand breaks (DSBs) in the Tcra site of the translocation are Rag-generated, whereas the Myc-Pvt1 DSBs are not. Aberrantly activated β-catenin redirects Tcf-1 binding to novel DNA sites to alter chromatin accessibility and down-regulate genome-stability pathways. Impaired homologous recombination (HR) DNA repair and replication checkpoints lead to retention of DSBs that promote translocations and transformation of double-positive (DP) thymocytes. The resulting lymphomas, which resemble human T cell acute lymphoblastic leukemia (T-ALL), are sensitive to PARP inhibitors (PARPis). Our findings indicate that aberrant β-catenin signaling contributes to translocations in thymocytes by guiding Tcf-1 to promote the generation and retention of replication-induced DSBs allowing their coexistence with Rag-generated DSBs. Thus, PARPis could offer therapeutic options in hematologic malignancies with active Wnt/β-catenin signaling | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a T-ALL | |
| 650 | 4 | |a Tcf-1 | |
| 650 | 4 | |a genomic instability | |
| 650 | 4 | |a β-catenin | |
| 650 | 7 | |a Hepatocyte Nuclear Factor 1-alpha |2 NLM | |
| 650 | 7 | |a Hnf1a protein, mouse |2 NLM | |
| 650 | 7 | |a Myc protein, mouse |2 NLM | |
| 650 | 7 | |a PVT1 long-non-coding RNA, mouse |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-myc |2 NLM | |
| 650 | 7 | |a RNA, Long Noncoding |2 NLM | |
| 650 | 7 | |a beta Catenin |2 NLM | |
| 700 | 1 | |a Mathur, Priya |e verfasserin |4 aut | |
| 700 | 1 | |a Tracy, Melissa |e verfasserin |4 aut | |
| 700 | 1 | |a Mohsin, Azam |e verfasserin |4 aut | |
| 700 | 1 | |a Mondal, Soumi |e verfasserin |4 aut | |
| 700 | 1 | |a Quandt, Jasmin |e verfasserin |4 aut | |
| 700 | 1 | |a Hernandez, Kyle M |e verfasserin |4 aut | |
| 700 | 1 | |a Khazaie, Khashayarsha |e verfasserin |4 aut | |
| 700 | 1 | |a Dose, Marei |e verfasserin |4 aut | |
| 700 | 1 | |a Emmanuel, Akinola Olumide |e verfasserin |4 aut | |
| 700 | 1 | |a Gounari, Fotini |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Proceedings of the National Academy of Sciences of the United States of America |d 1915 |g 119(2022), 32 vom: 09. Aug., Seite e2201493119 |w (DE-627)NLM000008982 |x 1091-6490 |7 nnns |
| 773 | 1 | 8 | |g volume:119 |g year:2022 |g number:32 |g day:09 |g month:08 |g pages:e2201493119 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1073/pnas.2201493119 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 119 |j 2022 |e 32 |b 09 |c 08 |h e2201493119 | ||