A multiomic atlas identifies a treatment-resistant, bone marrow progenitor-like cell population in T cell acute lymphoblastic leukemia
Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to curing T cell acute lymphoblastic leukemia (T-ALL). While tumor heterogeneity has been implicated in treatment failure, the cellular and genetic factors contributing to resistance and relapse remain unknown. Here we linked tumor subpopulations with clinical outcome, created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic analysis to a diverse cohort of 40 T-ALL cases. We identified a bone marrow progenitor (BMP)-like leukemia subpopulation associated with treatment failure and poor overall survival. The single-cell-derived molecular signature of BMP-like blasts predicted poor outcome across multiple subtypes of T-ALL and revealed that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state. Through in silico and in vitro drug screenings, we identified a therapeutic vulnerability of BMP-like blasts to apoptosis-inducing agents including venetoclax. Collectively, our study establishes multiomic signatures for rapid risk stratification and targeted treatment of high-risk T-ALL.
Authors
- Gregory M. Chen (ORCID: https://orcid.org/0000-0002-4083-5083)
- Kai Tan (ORCID: https://orcid.org/0000-0002-9104-5567)
- Mignon L. Loh (ORCID: https://orcid.org/0000-0003-4099-4700)
- Brent Lee Wood (ORCID: https://orcid.org/0000-0001-7414-3969)
- Jianzhong Hu (ORCID: https://orcid.org/0000-0002-7548-5802)
- Nancy R. Zhang (ORCID: https://orcid.org/0000-0002-0880-5749)
- Rushabh Mehta (ORCID: https://orcid.org/0009-0003-6370-4689)
- Stephen P. Hunger (ORCID: https://orcid.org/0000-0002-5492-3957)
- Elizabeth A. Raetz (ORCID: https://orcid.org/0000-0002-8547-1658)
- David T. Teachey (ORCID: https://orcid.org/0000-0001-7373-8987)
- Lauren K. Meyer (ORCID: https://orcid.org/0000-0002-7603-8457)
- Gang Wu (ORCID: https://orcid.org/0000-0002-1678-5864)
- Petri Pölönen (ORCID: https://orcid.org/0000-0001-6128-9985)
- Lahari Uppuluri (ORCID: https://orcid.org/0000-0002-7217-892X)
- Wenbao Yu (ORCID: https://orcid.org/0000-0001-8860-2644)
- Rawan Shraim (ORCID: https://orcid.org/0009-0005-5350-3386)
- Haley Newman (ORCID: https://orcid.org/0000-0002-3022-8052)
- Alexander Li (ORCID: https://orcid.org/0009-0003-9852-0855)
- Jacqueline Peng (ORCID: https://orcid.org/0000-0001-6231-3684)
- Anusha Thadi (ORCID: https://orcid.org/0000-0002-1271-0398)
- Yangyang Ding (ORCID: https://orcid.org/0000-0003-1588-2571)
- David B. Frank (ORCID: https://orcid.org/0000-0002-3064-2069)
- Changya Chen (ORCID: https://orcid.org/0000-0003-4421-2462)
- Charles Grenfell Mullighan (ORCID: https://orcid.org/0000-0002-1871-1850)
- Satoshi Yoshimura (ORCID: https://orcid.org/0000-0003-3490-2101)
- David Wei Wu (ORCID: https://orcid.org/0000-0001-6197-7091)
- Yusha Sun (ORCID: https://orcid.org/0000-0003-4835-3000)
- Jun J. Yang (ORCID: https://orcid.org/0000-0002-0770-9659)
- Kimberly P. Dunsmore (ORCID: https://orcid.org/0000-0002-6631-5174)
- Shovik Bandyopadhyay (ORCID: https://orcid.org/0000-0003-3919-3914)
- Stanley Pounds (ORCID: https://orcid.org/0000-0002-9167-2114)
- Ti‐Cheng Chang (ORCID: https://orcid.org/0000-0001-5302-9147)
- Stuart S. Winter (ORCID: https://orcid.org/0000-0003-3583-7727)
- Caroline Diorio (ORCID: https://orcid.org/0000-0002-8005-3836)
- Omar Elghawy (ORCID: https://orcid.org/0000-0002-0786-8035)
- Tiffaney L. Vincent (ORCID: https://orcid.org/0009-0004-6147-7088)
- William L. Carroll (ORCID: https://orcid.org/0000-0003-1550-4167)
- Kathrin M. Bernt (ORCID: https://orcid.org/0000-0002-0691-356X)
- Chia-Hui Chen (ORCID: https://orcid.org/0000-0001-5239-1574)
- Chi-Yun Wu (ORCID: https://orcid.org/0000-0003-4956-4133)
- Meenakshi Devidas (ORCID: https://orcid.org/0000-0002-1099-3478)
- Joseph S. Tumulty (ORCID: https://orcid.org/0000-0001-7531-2066)
- Elizabeth Y. Li
- Zhiguo Chen (ORCID: https://orcid.org/0000-0002-8913-8035)
- Alice Wang (ORCID: https://orcid.org/0000-0002-1789-8561)
- Jessica Xu (ORCID: https://orcid.org/0000-0003-2587-9587)
- Tristan Lim (ORCID: https://orcid.org/0000-0002-3798-5400)
- Kyung Jin Ahn (ORCID: https://orcid.org/0000-0002-4184-482X)
- Jonathan Sussman (ORCID: https://orcid.org/0000-0002-3057-3550)
- Jason Xu
- Miles Hsu
- Damjan Karanfilovski
Institutions
- Seattle Children's Hospital (US)
- St. Jude Children's Research Hospital (US)
- Children's Hospital of Philadelphia (US)
- Children's Hospital of Los Angeles (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Yale University (US)
- University of Florida (US)
- NYU Langone Health (US)
- University of Virginia Children's Hospital (US)
- Seattle Children's Hospital (US)
- Children's Minnesota (US)
- Institute of Hematology & Blood Diseases Hospital (CN)
- University of Minnesota Children's Hospital (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Cancer
- Published
- 2024-11-25
- DOI
- https://doi.org/10.1038/s43018-024-00863-5
- Citations
- 20
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 10.86
Funders
- Pennsylvania Department of Health
- Leukemia and Lymphoma Society
- St. Baldrick's Foundation
- National Institutes of Health
- Hyundai Hope On Wheels