Acute myeloid leukemia-derived bone marrow mesenchymal cells exhibit improved support for leukemic cell proliferation

Mariane Cristina do Nascimento; Diego A Pereira-Martins; João Agostinho Machado-Neto; Eduardo M Rego

doi:10.1016/j.htct.2023.10.007

Acute myeloid leukemia-derived bone marrow mesenchymal cells exhibit improved support for leukemic cell proliferation

Hematol Transfus Cell Ther. 2023 Dec 27:S2531-1379(23)02602-0. doi: 10.1016/j.htct.2023.10.007. Online ahead of print.

Authors

Mariane Cristina do Nascimento¹, Diego A Pereira-Martins¹, João Agostinho Machado-Neto², Eduardo M Rego³

Affiliations

¹ Center for Cell-Based Therapy, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil; Hematology Division, LIM31, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil.
² Instituto de Ciências Biomédicas da Universidade de São Paulo (ICB-USP), São Paulo, SP, Brazil.
³ Center for Cell-Based Therapy, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil; Hematology Division, LIM31, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil. Electronic address: eduardo.rego@fm.usp.br.

PMID: 38307829
DOI: 10.1016/j.htct.2023.10.007

Abstract

Introduction: The bone marrow (BM) microenvironment plays a significant role in acute myeloid leukemia (AML) genesis and there is evidence that BM mesenchymal stromal cells (BMMSCs) can support leukemia progenitor cell proliferation and survival and provide resistance to cytotoxic therapies.

Hypothesis and method: Nevertheless, currently unknown are the relevance of the spatial localization of AML cells relative to the BMMSCs and whether BMMSCs from patients with AML and healthy subjects have similar properties. To address these issues, we performed a differential gene expression analysis using RNA-sequencing data generated from healthy donors (HDs) and leukemic BMMSCs.

Results: The Gene Set Enrichment Analysis (GSEA) revealed that leukemic BMMSCs were associated with the terms "positive regulation of cell cycle", "angiogenesis" and "signaling by the estimated glomerular filtration rate (eGFR)", whereas healthy donor (HD)-derived BMMSCs were associated with "programmed cell death in response to the reactive oxygen species (ROS)", "negative regulation of the cytochrome C from the mitochondria" and "interferon signaling". Next, we evaluated the mitochondrial superoxide production in AML cells in a co-culture layered model. The superoxide production was reduced in leukemic cells in close contact (adhered to the surface or beneath the cell layer) with BMMSCs, indicating lower oxidative stress.

Conclusion: Taken together, our results suggest that AML-derived BMMSCs are transcriptionally rewired and can reduce the metabolic stress of leukemic cells.

Keywords: Acute myeloid leukemia; Bone marrow microenvironment; Cell proliferation; Metabolism.