Cellular taxonomy of the preleukemic bone marrow niche of acute myeloid leukemia
Leukemias arise from recurrent clonal mutations in hematopoietic stem/progenitor cells (HSPCs) that cause profound changes in the bone marrow microenvironment (BMM) favoring leukemic stem cell (LSC) growth over normal HSPCs. Understanding the cross talk between preleukemic mutated HSPCs and the BMM is critical to develop novel therapeutic strategies to prevent leukemogenesis. We hypothesize that preleukemic-LSCs (pLSCs) induce BMM changes critical for leukemogenesis. Using our AML-murine model, we performed single-cell RNA-sequencing of preleukemic BMM (pBMM) cells. We found normal HSC (nHSC)-regulating LepR+ mesenchymal stem cells, and endothelial cells were decreased, along with increases in CD55+ fibroblasts and pericytes. Preleukemic CD55+ fibroblasts had higher proliferation rates and decreased collagen expression, suggesting extracellular matrix remodeling during leukemogenesis. Importantly, co-culture assays found preleukemic CD55+ fibroblasts expanded pLSCs significantly over nHSCs. In conclusion, we have identified a distinct pBMM and a novel CD55+ fibroblast population that is expanded in pBMM that promote fitness of pLSCs over nHSCs.
Authors
- Bethany L. Mundy-Bosse (ORCID: https://orcid.org/0009-0004-7397-7653)
- Ozlen Balcioglu (ORCID: https://orcid.org/0000-0002-4320-6880)
- Linde A. Miles (ORCID: https://orcid.org/0000-0003-3578-2842)
- Amog P. Urs (ORCID: https://orcid.org/0000-0002-7818-2460)
- Chinmayee Goda (ORCID: https://orcid.org/0000-0002-3718-585X)
- Robert L. Bowman (ORCID: https://orcid.org/0000-0002-8294-8748)
- Aaron D. Viny (ORCID: https://orcid.org/0000-0001-7039-0110)
- Malith Karunasiri
- Elaine R. Mardis (ORCID: https://orcid.org/0000-0002-5892-1553)
- Ramiro Garzon (ORCID: https://orcid.org/0000-0003-0456-3161)
- Guido Marcucci (ORCID: https://orcid.org/0000-0002-3983-5908)
- Lalit Sehgal (ORCID: https://orcid.org/0000-0002-1151-5427)
- Elizabeth A.R. Garfinkle (ORCID: https://orcid.org/0000-0002-7292-4347)
- Alexander Rudich (ORCID: https://orcid.org/0009-0005-1264-9936)
- Nisarg J. Shah
- Katherine E. Miller (ORCID: https://orcid.org/0000-0003-1054-0476)
- Ashley Wooten
- Sadie Chidester
- Yzen Al-Marrawi
- Sanjay Kanna
- Yaphet Bustos
- Bin Zhang (ORCID: https://orcid.org/0000-0003-4703-7524)
- Wenjun Li (ORCID: https://orcid.org/0000-0003-1152-5016)
- Adrienne M. Dorrance
- Erin Korn
- Rohan Kulkarni
Institutions
- Cincinnati Children's Hospital Medical Center (US)
- Nationwide Children's Hospital (US)
- University of Utah (US)
- Huntsman Cancer Institute (US)
- City of Hope (US)
- Cancer Genetics (United States) (US)
- Beckman Research Institute
- The Ohio State University (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Leukemia
- Published
- 2024-10-02
- DOI
- https://doi.org/10.1038/s41375-024-02415-3
- Citations
- 6
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 2.73