Bone marrow stromal cells from MDS and AML patients show increased adipogenic potential with reduced Delta-like-1 expression

Abstract

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell disorders with a poor prognosis, especially for elderly patients. Increasing evidence suggests that alterations in the non-hematopoietic microenvironment (bone marrow niche) can contribute to or initiate malignant transformation and promote disease progression. One of the key components of the bone marrow (BM) niche are BM stromal cells (BMSC) that give rise to osteoblasts and adipocytes. It has been shown that the balance between these two cell types plays an important role in the regulation of hematopoiesis. However, data on the number of BMSC and the regulation of their differentiation balance in the context of hematopoietic malignancies is scarce. We established a stringent flow cytometric protocol for the prospective isolation of a CD73+ CD105+ CD271+ BMSC subpopulation from uncultivated cryopreserved BM of MDS and AML patients as well as age-matched healthy donors. BMSC from MDS and AML patients showed a strongly reduced frequency of CFU-F (colony forming unit-fibroblast). Moreover, we found an altered phenotype and reduced replating efficiency upon passaging of BMSC from MDS and AML samples. Expression analysis of genes involved in adipo- and osteogenic differentiation as well as Wnt- and Notch-signalling pathways showed significantly reduced levels of DLK1, an early adipogenic cell fate inhibitor in MDS and AML BMSC. Matching this observation, functional analysis showed significantly increased in vitro adipogenic differentiation potential in BMSC from MDS and AML patients. Overall, our data show BMSC with a reduced CFU-F capacity, and an altered molecular and functional profile from MDS and AML patients in culture, indicating an increased adipogenic lineage potential that is likely to provide a disease-promoting microenvironment.

Emerging Bone Marrow Microenvironment-Driven Mechanisms of Drug Resistance in Acute Myeloid Leukemia: Tangle or Chance?

“…The ‘FA store’ is particularly rich in AML. BM stromal cells are reduced in AML [ 86 , 87 ], but adipocytes are abundant and increase in elderly patients [ 88 , 89 ]. Tabe et al [ 60 ] have recently discussed the mechanisms by which the stromal BM microenvironment and specifically adipocytes support leukemic cell survival and metabolic demand of FA, as well as the therapeutic potential of fatty acid oxidation (FAO) inhibitors.…”

Nature or Nurture? Role of the Bone Marrow Microenvironment in the Genesis and Maintenance of Myelodysplastic Syndromes

“…Several observations relating to MSCs in patients with MDS, such as altered expression of adhesion proteins, PI3K/AKT signalling, WNT/β-catenin signalling have implied that these cells have animportant role in sustaining the MDS disease phenotype (Figure 2) [71][72][73][74]78,80,81]. MDS patient derived MSCs seems to have reduced clonogenicity, increased senescence and also defects in adipogenic as well as osteogenic differentiation potential, especially in high-risk categories such as refractory anaemia with excess blasts [71,74,78,82,83]. Focal adhesion kinase that regulates cell signalling networks including survival, proliferation, differentiation, mobility, and adhesion, is dysregulated in MDS MSCs and has been corelated with increased senescence and dysfunctional differentiation [72,83].…”

The Hematopoietic Bone Marrow Niche Ecosystem

“…Indeed, cultured MSCs from MDS patients show inflammatory changes compared to healthy MSCs (Medyouf et al, 2014). Prospectively isolated non-cultured CD271 + CD105 + MDS-MSCs also show a significant inflammatory signature (Chen et al, 2016) with increased adipogenic potential (Weickert et al, 2021), showing that stromal inflammation does not depend on cell culture and may be the result of BM niche remodeling.…”