Cellular taxonomy of the preleukemic bone marrow niche of acute myeloid leukemia

Chinmayee Goda; Rohan Kulkarni; Yaphet Bustos; Wenjun Li; Alexander Rudich; Ozlen Balcioglu; Sadie Chidester; Amog P. Urs; Malith Karunasiri; Yzen Al-Marrawi; Erin Korn; Sanjay Kanna; Elizabeth A.R. Garfinkle; Nisarg Shah; Ashley Wooten; Bethany Mundy-Bosse; Lalit Sehgal; Bin Zhang; Guido Marcucci; Elaine R. Mardis; Ramiro Garzon; Robert L. Bowman; Aaron D. Viny; Linde A. Miles; Katherine E. Miller; Adrienne Dorrance

doi:10.1038/s41375-024-02415-3

Cellular taxonomy of the preleukemic bone marrow niche of acute myeloid leukemia

Chinmayee Goda, Rohan Kulkarni, Yaphet Bustos, Wenjun Li, Alexander Rudich, Ozlen Balcioglu, Sadie Chidester, Amog P. Urs, Malith Karunasiri, Yzen Al-Marrawi, Erin Korn, Sanjay Kanna, Elizabeth A.R. Garfinkle, Nisarg Shah, Ashley Wooten, Bethany Mundy-Bosse, Lalit Sehgal, Bin Zhang, Guido Marcucci, Elaine R. MardisRamiro Garzon, Robert L. Bowman, Aaron D. Viny, Linde A. Miles, Katherine E. Miller, Adrienne Dorrance

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Journal	Leukemia
DOIs	https://doi.org/10.1038/s41375-024-02415-3
State	Accepted/In press - 2024

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Goda, C., Kulkarni, R., Bustos, Y., Li, W., Rudich, A., Balcioglu, O., Chidester, S., Urs, A. P., Karunasiri, M., Al-Marrawi, Y., Korn, E., Kanna, S., Garfinkle, E. A. R., Shah, N., Wooten, A., Mundy-Bosse, B., Sehgal, L., Zhang, B., Marcucci, G., ... Dorrance, A. (Accepted/In press). Cellular taxonomy of the preleukemic bone marrow niche of acute myeloid leukemia. Leukemia. https://doi.org/10.1038/s41375-024-02415-3

@article{c68f2eac62594244a3b2cadaa37d38a4,

title = "Cellular taxonomy of the preleukemic bone marrow niche of acute myeloid leukemia",

abstract = "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.",

author = "Chinmayee Goda and Rohan Kulkarni and Yaphet Bustos and Wenjun Li and Alexander Rudich and Ozlen Balcioglu and Sadie Chidester and Urs, {Amog P.} and Malith Karunasiri and Yzen Al-Marrawi and Erin Korn and Sanjay Kanna and Garfinkle, {Elizabeth A.R.} and Nisarg Shah and Ashley Wooten and Bethany Mundy-Bosse and Lalit Sehgal and Bin Zhang and Guido Marcucci and Mardis, {Elaine R.} and Ramiro Garzon and Bowman, {Robert L.} and Viny, {Aaron D.} and Miles, {Linde A.} and Miller, {Katherine E.} and Adrienne Dorrance",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

doi = "10.1038/s41375-024-02415-3",

language = "English",

journal = "Leukemia",

issn = "0887-6924",

}

Goda, C, Kulkarni, R, Bustos, Y, Li, W, Rudich, A, Balcioglu, O, Chidester, S, Urs, AP, Karunasiri, M, Al-Marrawi, Y, Korn, E, Kanna, S, Garfinkle, EAR, Shah, N, Wooten, A, Mundy-Bosse, B , Sehgal, L, Zhang, B, Marcucci, G, Mardis, ER, Garzon, R, Bowman, RL, Viny, AD, Miles, LA, Miller, KE & Dorrance, A 2024, 'Cellular taxonomy of the preleukemic bone marrow niche of acute myeloid leukemia', Leukemia. https://doi.org/10.1038/s41375-024-02415-3

TY - JOUR

T1 - Cellular taxonomy of the preleukemic bone marrow niche of acute myeloid leukemia

AU - Goda, Chinmayee

AU - Kulkarni, Rohan

AU - Bustos, Yaphet

AU - Li, Wenjun

AU - Rudich, Alexander

AU - Balcioglu, Ozlen

AU - Chidester, Sadie

AU - Urs, Amog P.

AU - Karunasiri, Malith

AU - Al-Marrawi, Yzen

AU - Korn, Erin

AU - Kanna, Sanjay

AU - Garfinkle, Elizabeth A.R.

AU - Shah, Nisarg

AU - Wooten, Ashley

AU - Mundy-Bosse, Bethany

AU - Sehgal, Lalit

AU - Zhang, Bin

AU - Marcucci, Guido

AU - Mardis, Elaine R.

AU - Garzon, Ramiro

AU - Bowman, Robert L.

AU - Viny, Aaron D.

AU - Miles, Linde A.

AU - Miller, Katherine E.

AU - Dorrance, Adrienne

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85205428053&partnerID=8YFLogxK

U2 - 10.1038/s41375-024-02415-3

DO - 10.1038/s41375-024-02415-3

M3 - Article

C2 - 39358541

AN - SCOPUS:85205428053

SN - 0887-6924

JO - Leukemia

JF - Leukemia

ER -

Cellular taxonomy of the preleukemic bone marrow niche of acute myeloid leukemia

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