Identification of cells of leukemic stem cell origin with non-canonical regenerative properties

Cameron G Hollands; Allison L Boyd; Xueli Zhao; Jennifer C Reid; Charisa Henly; Amro ElRafie; David Boylan; Emily Broder; Olivia Kalau; Paige Johnson; Alyssa Mark; Jamie McNicol; Anargyros Xenocostas; Tobias Berg; Ronan Foley; Michael Trus; Brian Leber; Alejandro Garcia-Horton; Clinton Campbell; Mickie Bhatia

doi:10.1016/j.xcrm.2024.101485

Identification of cells of leukemic stem cell origin with non-canonical regenerative properties

Cell Rep Med. 2024 Apr 16;5(4):101485. doi: 10.1016/j.xcrm.2024.101485. Epub 2024 Apr 5.

Authors

Cameron G Hollands¹, Allison L Boyd¹, Xueli Zhao¹, Jennifer C Reid¹, Charisa Henly¹, Amro ElRafie¹, David Boylan¹, Emily Broder¹, Olivia Kalau¹, Paige Johnson¹, Alyssa Mark¹, Jamie McNicol¹, Anargyros Xenocostas², Tobias Berg³, Ronan Foley³, Michael Trus⁴, Brian Leber⁴, Alejandro Garcia-Horton³, Clinton Campbell⁴, Mickie Bhatia⁵

Affiliations

¹ Michael G. DeGroote School of Medicine, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
² Department of Medicine, Division of Hematology, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 3K7, Canada; Hematology Exploration and Applications in Leukemia (HEAL) Program, Hamilton, ON, Canada.
³ Hematology Exploration and Applications in Leukemia (HEAL) Program, Hamilton, ON, Canada; Department of Oncology, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁴ Hematology Exploration and Applications in Leukemia (HEAL) Program, Hamilton, ON, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁵ Michael G. DeGroote School of Medicine, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada; Hematology Exploration and Applications in Leukemia (HEAL) Program, Hamilton, ON, Canada. Electronic address: mbhatia@mcmaster.ca.

Abstract

Despite most acute myeloid leukemia (AML) patients entering remission following chemotherapy, outcomes remain poor due to surviving leukemic cells that contribute to relapse. The nature of these enduring cells is poorly understood. Here, through temporal single-cell transcriptomic characterization of AML hierarchical regeneration in response to chemotherapy, we reveal a cell population: AML regeneration enriched cells (RECs). RECs are defined by CD74/CD68 expression, and although derived from leukemic stem cells (LSCs), are devoid of stem/progenitor capacity. Based on REC in situ proximity to CD34-expressing cells identified using spatial transcriptomics on AML patient bone marrow samples, RECs demonstrate the ability to augment or reduce leukemic regeneration in vivo based on transfusion or depletion, respectively. Furthermore, RECs are prognostic for patient survival as well as predictive of treatment failure in AML cohorts. Our study reveals RECs as a previously unknown functional catalyst of LSC-driven regeneration contributing to the non-canonical framework of AML regeneration.

Keywords: Regen71; acute myeloid leukemia; chemotherapy; injury; leukemia stem cells; non-canonical regeneration; regeneration enriched cells; relapse.

MeSH terms

Gene Expression Profiling*
Humans
Leukemia, Myeloid, Acute* / drug therapy
Prognosis
Stem Cells / metabolism