The hematopoietic stem cell MYB enhancer is essential for and recurrently amplified during T cell leukemogenesis

There is an urgent need to find targeted agents for T cell acute lymphoblastic leukemia (T-ALL). NOTCH1 is the most frequently mutated oncogene in T-ALL, but clinical trials showed that pan-Notch inhibitors caused dose-limiting toxicities. Thus, we shifted our focus to ETS1, which is one of the transcription factors that most frequently co-bind Notch-occupied regulatory elements in the T-ALL context. To identify the most essential enhancers, we performed a genome-wide CRISPRi screen of the strongest ETS1-dependent regulatory elements. The top-ranked element is located in an intron of AHI1 that interacts with the MYB promoter and is amplified with MYB in approximately 8.5% of patients with T-ALL. Using mouse models, we showed that this enhancer promoted self-renewal of hematopoietic stem cells and T cell leukemogenesis, maintained early T cell precursors, and restrained myeloid expansion with aging. We named this enhancer the hematopoietic stem cell MYB enhancer (H-Me). The H-Me showed limited activity and function in committed T cell progenitors but was accessed during leukemogenesis. In one T-ALL context, ETS1 bound the ETS motif in the H-Me to recruit cBAF to promote chromatin accessibility and activation. ETS1 or cBAF degraders impaired H-Me function. Thus, we identified a targetable stem cell element that was co-opted for T cell transformation.

Authors

Institutions

Publication Details

Journal
Journal of Clinical Investigation
Published
2025-10-23
DOI
https://doi.org/10.1172/jci187998
Primary Topic
Acute Lymphoblastic Leukemia research
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

The hematopoietic stem cell MYB enhancer is essential for and recurrently amplified during T cell leukemogenesis

Ashwin Iyer, Felipe da Veiga Leprevost, Elizabeth Choe, David T. Teachey et al.
Journal of Clinical Investigation
Acute Lymphoblastic Leukemia research
article

The hematopoietic stem cell MYB enhancer is essential for and recurrently amplified during T cell leukemogenesis

Ashwin Iyer, Felipe da Veiga Leprevost, Elizabeth Choe, David T. Teachey, Petri Pölönen, Carea Mullin, Mark Y. Chiang, Paul M. Evans, Kelly R. Barnett, Annie Wang, Cher Sha, Ashley F. Melnick, Charles Grenfell Mullighan, Anna C. McCarter, Marcin Cieślik, Rami Khoriaty, Alexander C. Monovich, Yamei Deng, Linda C. Samuelson, Rohan Kodgule, Karena Lin, Koral Campbell, Russell J.H. Ryan, Alexey I. Nesvizhskii, Sarah Khan, Daniel Savic, Theresa M. Keeley, Qing Li, Qing Wang, Morgan Jones, Shannon Liang, Zeel Shukla, Jannaldo Nieves-Salva
article en

Abstract

There is an urgent need to find targeted agents for T cell acute lymphoblastic leukemia (T-ALL). NOTCH1 is the most frequently mutated oncogene in T-ALL, but clinical trials showed that pan-Notch inhibitors caused dose-limiting toxicities. Thus, we shifted our focus to ETS1, which is one of the transcription factors that most frequently co-bind Notch-occupied regulatory elements in the T-ALL context. To identify the most essential enhancers, we performed a genome-wide CRISPRi screen of the strongest ETS1-dependent regulatory elements. The top-ranked element is located in an intron of AHI1 that interacts with the MYB promoter and is amplified with MYB in approximately 8.5% of patients with T-ALL. Using mouse models, we showed that this enhancer promoted self-renewal of hematopoietic stem cells and T cell leukemogenesis, maintained early T cell precursors, and restrained myeloid expansion with aging. We named this enhancer the hematopoietic stem cell MYB enhancer (H-Me). The H-Me showed limited activity and function in committed T cell progenitors but was accessed during leukemogenesis. In one T-ALL context, ETS1 bound the ETS motif in the H-Me to recruit cBAF to promote chromatin accessibility and activation. ETS1 or cBAF degraders impaired H-Me function. Thus, we identified a targetable stem cell element that was co-opted for T cell transformation.

Journal of Clinical InvestigationVol. 136(1)
St. Jude Children's Research Hospital (US), Children's Hospital of Philadelphia (US), Baylor College of Medicine (US), Regeneron (United States) (US), Washington University in St. Louis (US), University of Michigan (US), Michigan Medicine (US), Stanford Medicine (US), Pharmaceutical Biotechnology (Czechia) (CZ), Saint Louis University (US), Stanford University (US)
Rally Foundation, St. Jude Children's Research Hospital, American Lebanese Syrian Associated Charities, National Institutes of Health, Horace H. Rackham School of Graduate Studies, University of Michigan
Openalex Percentile: Top 60%
Acute Lymphoblastic Leukemia research
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.