3D chromatin hubs as regulatory units of identity and survival in human acute leukemia Journal Article
| Authors: | Gambi, G.; Boccalatte, F.; Rodriguez Hernaez, J.; Lin, Z.; Nadorp, B.; Polyzos, A.; Tan, J.; Avrampou, K.; Inghirami, G.; Kentsis, A.; Apostolou, E.; Aifantis, I.; Tsirigos, A. |
| Article Title: | 3D chromatin hubs as regulatory units of identity and survival in human acute leukemia |
| Abstract: | Cancer progression involves genetic and epigenetic changes that disrupt chromatin 3D organization, affecting enhancer-promoter interactions and promoting growth. Here, we provide an integrative approach, combining chromatin conformation, accessibility, and transcription analysis, validated by in silico and CRISPR-interference screens, to identify relevant 3D topologies in pediatric T cell leukemia (T-ALL and ETP-ALL). We characterize 3D hubs as regulatory centers for oncogenes and disease markers, linking them to biological processes like cell division, inflammation, and stress response. Single-cell mapping reveals heterogeneous gene activation in discrete epigenetic clones, aiding in patient stratification for relapse risk after chemotherapy. Finally, we identify MYB as a 3D hub regulator in leukemia cells and show that the targeting of key regulators leads to hub dissolution, thereby providing a novel and effective anti-leukemic strategy. Overall, our work demonstrates the relevance of studying oncogenic 3D hubs to better understand cancer biology and tumor heterogeneity and to propose novel therapeutic strategies. © 2024 Elsevier Inc. |
| Keywords: | cancer chemotherapy; cancer survival; child; controlled study; leukemia; human cell; promoter region; genetics; nonhuman; disease marker; recurrence risk; phenotype; metabolism; cell division; cd34 antigen; apoptosis; gene expression; inflammation; pathology; cell line, tumor; acute lymphoblastic leukemia; high risk patient; cell heterogeneity; oncogenes; gene expression regulation; oncogene; gene activation; regulatory mechanism; pre t lymphocyte; minimal residual disease; epigenetics; chromatin; epigenesis, genetic; histone h3; leukemia cell; tumor cell line; chromosome translocation; down regulation; upregulation; conformation; computer model; genetic epigenesis; t cell leukemia; marker gene; cell stress; notch1 receptor; chromosome 14q; chromatin structure; gene expression regulation, leukemic; precursor t-cell lymphoblastic leukemia-lymphoma; transcription initiation site; enhancer region; heterogeneity; single cell analysis; single-cell analysis; protein myb; gene knockdown; humans; human; article; rna sequencing; modules; myb; t cell acute lymphoblastic leukemia; crispr-cas9 system; apoptosis rate; mixed phenotype acute leukemia; jurkat cell line; hubs; chromatin immunoprecipitation sequencing; hichip; scatac; cutll1 cell line |
| Journal Title: | Molecular Cell |
| Volume: | 85 |
| Issue: | 1 |
| ISSN: | 1097-2765 |
| Publisher: | Cell Press |
| Date Published: | 2025-01-02 |
| Start Page: | 42 |
| End Page: | 60.e7 |
| Language: | English |
| DOI: | 10.1016/j.molcel.2024.11.040 |
| PUBMED: | 39719705 |
| PROVIDER: | scopus |
| PMCID: | PMC11934262 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
