Single-cell panleukemia signatures of HSPC-like blasts predict drug response and clinical outcome
The critical role of leukemia-initiating cells as a therapy-resistant population in myeloid leukemia is well established. However, the molecular signatures of such cells in acute lymphoblastic leukemia remain underexplored. Moreover, their role in therapy response and patient prognosis is yet to be systematically investigated across various types of acute leukemia. We used single-cell multiomics to analyze diagnostic specimens from 96 pediatric patients with acute lymphoblastic, myeloid, and lineage-ambiguous leukemias. Through the integration of single-cell multiomics with extensive bulk RNA sequencing and clinical data sets, we uncovered a prevalent, chemotherapy-resistant subpopulation that resembles hematopoietic stem and progenitor cells (HSPC-like) and is associated with poor clinical outcomes across all subtypes investigated. We identified a core transcriptional regulatory network (TRN) in HSPC-like blasts that is combinatorially controlled by HOXA/AP1/CEBPA. This TRN signature can predict chemotherapy response and long-term clinical outcomes. We identified shared potential therapeutic targets against HSPC-like blasts, including FLT3, BCL2, and the PI3K pathway. Our study provides a framework for linking intratumoral heterogeneity with therapy response, patient outcomes, and the discovery of new therapeutic targets for pediatric acute leukemias.
Authors
- 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)
- 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)
- Gongping Shi (ORCID: https://orcid.org/0000-0001-8432-8553)
- Fatemeh Alikarami (ORCID: https://orcid.org/0000-0002-3600-9192)
- Petri Pölönen (ORCID: https://orcid.org/0000-0001-6128-9985)
- Lahari Uppuluri (ORCID: https://orcid.org/0000-0002-7217-892X)
- Austin Yang
- Wenbao Yu (ORCID: https://orcid.org/0000-0001-8860-2644)
- Andrew D. Hughes (ORCID: https://orcid.org/0000-0002-1251-2404)
- Rawan Shraim (ORCID: https://orcid.org/0009-0005-5350-3386)
- Haley Newman (ORCID: https://orcid.org/0000-0002-3022-8052)
- Jacqueline Peng (ORCID: https://orcid.org/0000-0001-6231-3684)
- 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)
- Jun J. Yang (ORCID: https://orcid.org/0000-0002-0770-9659)
- Shovik Bandyopadhyay (ORCID: https://orcid.org/0000-0003-3919-3914)
- Stanley Pounds (ORCID: https://orcid.org/0000-0002-9167-2114)
- Caroline Diorio (ORCID: https://orcid.org/0000-0002-8005-3836)
- Elizabeth Y Li (ORCID: https://orcid.org/0000-0001-9501-2263)
- Tiffaney L. Vincent (ORCID: https://orcid.org/0009-0004-6147-7088)
- Tori J. Fuller (ORCID: https://orcid.org/0000-0002-5506-260X)
- Kathrin M. Bernt (ORCID: https://orcid.org/0000-0002-0691-356X)
- Chia-Hui Chen (ORCID: https://orcid.org/0000-0001-5239-1574)
- Joseph S. Tumulty (ORCID: https://orcid.org/0000-0001-7531-2066)
- Jonathan Sussman (ORCID: https://orcid.org/0000-0002-3057-3550)
- Theresa Ryan
- Xiaohuan Qin
- Jason Xu
Institutions
- Seattle Children's Hospital (US)
- St. Jude Children's Research Hospital (US)
- Amgen (United States) (US)
- Children's Hospital of Philadelphia (US)
- Children's Hospital of Los Angeles (US)
- Johns Hopkins University (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- University of Washington (US)
- Johns Hopkins Medicine (US)
- Yale University (US)
- NYU Langone Health (US)
- Seattle Children's Hospital (US)
- Center for Cancer and Blood Disorders (US)
- Institute of Hematology & Blood Diseases Hospital (CN)
- Sidney Kimmel Comprehensive Cancer Center (US)
- New York University (US)
- University of Pennsylvania (US)
- Philadelphia University (US)
Publication Details
- Journal
- Blood
- Published
- 2025-03-16
- DOI
- https://doi.org/10.1182/blood.2024027270
- Citations
- 10
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 17.70