Stephanie Xie

At A Glance

• Hematopoietic stem cells (HSCs): We study how long-term HSCs maintain self-renewal, differentiation, and quiescence under both normal and stress conditions to ensure blood system homeostasis
• Role of lipid metabolism: Our research examines how sphingolipids interact with stemness regulatory programs, including inflammatory and proteostatic pathways, to influence cell fate in normal and leukemic stem cells.
• Clinical impact: We work to translate insights into lipid-stemness interactions into strategies that improve hematopoietic stem cell transplantation and develop targeted therapies for acute myeloid leukemia (AML).

Short Bio

Dr. Stephanie Xie is a Scientist at Princess Margaret Cancer Centre. The Xie lab studies inflammatory and metabolic stress in human hematopoietic stem cells and leukemia stem cells. By understanding how stress promotes aging and cancer risk, the group aims to discover novel cancer prevention strategies.

Dr. Xie completed her Ph.D. in cell biology under the supervision of a leading expert in cell division, Dr. Peter Sorger, at the Massachusetts Institute of Technology. Her work in the Sorger lab focused on testing Theodore Boveri’s seminal hypothesis that abnormal chromosome number would be sufficient to drive tumorigenesis. She then undertook postdoctoral training at Massachusetts General Hospital in the laboratory of Dr. David Scadden, a preeminent expert in murine hematopoietic stem cells (HSCs). There she tackled the complex role of metabolic regulatory circuitry in HSC fate decisions at homeostasis and during aging. Her work has provided fundamental insights into basic cell processes in HSCs at the highest level including showing the importance of Lkb1 to enter and exit quiescence by altering lipid and nucleotide metabolism, independent of AML-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR). She also showed that HSC fitness during aging is dependent on the regulation of metabolic stress through the sirtuin Sirt3.

Following this work, Dr. Xie pursued further postdoctoral training with Dr. John Dick at UHN, who pioneered the xenograft transplantation assay and has made seminal findings on human HSCs and leukemia stem cells (LSCs). Her work revealed new insights into the role of lipid metabolism in human HSCs and LSCs with significant translational impact. She found that sphingolipids are distinct across the human blood hierarchy and inhibiting sphingolipid metabolism preserves HSC self-renewal during ex vivo expansion culture and thus has great translational implications to regenerative medicine. Mechanistically, modulating sphingolipids activates pro-survival proteostatic quality control pathways. Dr. Xie further discovered that modulating sphingolipid signaling was a novel leukemia therapy axis to target LSCs by potentiating inflammatory pathways and promote LSC differentiation in acute myeloid leukemia patient samples. Recently, Dr. Xie has been interrogating how inflammation ages human HSCs and the clinical implications to clonal advantage and cancer risk. She has been recognized for her work by the American Association of Cancer Research as a 2025 NextGen Star and currently serves on the American Society of Hematology Scientific Committee on Stem Cells and Regenerative Medicine.

Research Synopsis

Human long-term hematopoietic stem cells (LT-HSC) play a central role in meeting both homeostatic (e.g. ≧1011 blood cells daily) and stress-mediated demands due to their three functional hallmarks: self-renewal, multilineage differentiation, and capacity to remain quiescent for long periods of time. Upon cues to exit this dormant state, LT-HSC must respond and adapt their metabolism and nutrient uptake to meet increased bioenergetic demands for cell growth and differentiation. Simultaneously, the events underlying cellular and metabolic activation must also be suppressed within a subset of LT-HSC to enable re-entry into quiescence and ultimately maintain the LT-HSC pool through self-renewal and prevent malignancy. The demand-adapted regulatory circuits of these early steps of hematopoiesis are emerging and include the interplay of transcriptional, epigenetic and metabolic programs. We have identified a particular class of lipids, sphingolipids, that intersects with stemness regulatory programs including inflammatory and proteostatic quality control pathways to regulate cell fate in human HSCs, and this differs in leukemia stem cells from patients with acute myeloid leukemia (AML). Lipids are emerging as regulators of normal adult stem cell fate in various tissues and in disease. Teasing out how lipids interact with stemness regulatory systems have great promise to yield strategies for improving HSC transplantation and targeting AML.

Recent Publications

1. Conti A, Giannetti K, Midena F, Beretta S, Gualandi N, De Marco R, Carsana E, Varesi A, Tavella T, Alessandrini L, Zarghamian P, Weber A, Ferrari S, Brombin C, Gilioli D, Della Volpe L, Xie SZ, Merelli I, Cathomen T, Naldini L, Di Micco R. Senescence and inflammation are unintended adverse consequences of CRISPR- Cas9/AAV6-mediated gene editing in hematopoietic stem cells. Cell Rep Med. 2025 Jun 17;6(6):102157. doi: 10.1016/j.xcrm.2025.102157. Epub 2025 Jun 3. PMID: 40466639; PMCID: PMC12208344.
2. Hosseini M, Voisin V, Chegini A, Varesi A, Cathelin S, Ayyathan DM, Liu ACH, Yang Y, Wang V, Maher A, Grignano E, Reisz JA, D'Alessandro A, Young K, Wu Y, Fiumara M, Ferrari S, Naldini L, Gaiti F, Pai S, Egan G, Schimmer AD, Bader GD, Dick JE, Xie SZ, Trowbridge JJ, Chan SM. Metformin reduces the competitive advantage of Dnmt3aR878H HSPCs. Nature. 2025 Jun; 642(8067):421-430. doi: 10.1038/s41586-025-08871-w. Epub 2025 Apr 16. PMID: 40240595.
3. Molteni R, Fiumara M, Campochiaro C, Alfieri R, Pacini G, Licari E, Tomelleri A, Diral E, Varesi A, Weber A, Quaranta P, Albano L, Gaddoni C, Basso-Ricci L, Stefanoni D, Alessandrini L, Degl'Innocenti S, Sanvito F, Bergonzi GM, Annoni A, Panigada M, Cantoni E, Canarutto D, Xie SZ, D'Alessandro A, Di Micco R, Aiuti A, Ciceri F, De Luca G, Dagna L, Matucci-Cerinic M, Merelli I, Cenci S, Scala S, Cavalli G, Naldini L, Ferrari S. Mechanisms of hematopoietic clonal dominance in VEXAS syndrome. Nat Med. 2025 Jun;31(6):1911-1924. doi: 10.1038/s41591-025-03623-9. Epub 2025 Apr 7. PMID: 40195449; PMCID: PMC12176642.
4. Chan EM, Chhabra Y, Dixon KO, Durbin AD, Färkkilä A, Jeyasekharan AD, Keckesova Z, Prensner JR, Wagenblast E, Xie SZ, Zhao D. Insights on Future Directions in Cancer Research from the 2025 AACR NextGen Stars. Cancer Discov. 2025 Apr 2;15(4):678-684. doi: 10.1158/2159-8290.CD-25-0239. PMID: 40170536.
5. Itkin T, Houghton S, Schreiner R, Lin Y, Badwe CR, Voisin V, Murison A, Seyedhassantehrani N, Kaufmann KB, Garcia-Prat L, Booth GT, Geng F, Liu Y, Gomez-Salinero JM, Shieh JH, Redmond D, Xiang JZ, Josefowicz SZ, Trapnell C, Pietras EM, Spencer JA, Levine R, Xiao W, Zangi L, Hadland B, Dick JE, Xie SZ, Rafii S. Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing. Nat Immunol. 2025 Mar;26(3):378-390. doi: 10.1038/s41590-025-02087-w. Epub 2025 Feb 25. PMID: 40000903.
6. Kaufmann KB, Xie SZ. Context and timing matters in acute myeloid leukemia: females are the superior hosts. Haematologica. 2025 May 1;110(5):1056-1058. doi: 10.3324/haematol.2024.287056. Epub 2025 Feb 6. PMID: 39911125; PMCID: PMC12050919.
7. Xie SZ. IRE1α-XBP1 moonlighting to restrict leukemia. Nat Immunol. 2025 Feb;26(2):157-158. doi: 10.1038/s41590-024-02061-y. PMID: 39825092.
8. Comazzetto S, Cassidy DL, DeVilbiss AW, Jeffery EC, Ottesen BR, Reyes AR, Paul A, Bansal S, Xie SZ, Muh S, Mathews TP, Chen B, Zhao Z, Morrison SJ. Ascorbate deficiency increases quiescence and self-renewal in hematopoietic stem cells and multipotent progenitors. Blood. 2025 Jan 2;145(1):114-126. doi: 10.1182/blood.2024024769. PMID: 39437548; PMCID: PMC11738029.
9. Jakobsen NA, Turkalj S, Zeng AGX, Stoilova B, Metzner M, Rahmig S, Nagree MS, Shah S, Moore R, Usukhbayar B, Angulo Salazar M, Gafencu GA, Kennedy A, Newman S, Kendrick BJL, Taylor AH, Afinowi-Luitz R, Gundle R, Watkins B, Wheway K, Beazley D, Murison A, Aguilar-Navarro AG, Flores-Figueroa E, Dakin SG, Carr AJ, Nerlov C, Dick JE, Xie SZ, Vyas P. Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging. Cell Stem Cell. 2024 Aug 1;31(8):1127-1144.e17. doi: 10.1016/j.stem.2024.05.010. Epub 2024 Jun 24. PMID: 38917807; PMCID: PMC11512683.