Stromal bone marrow fibroblasts and mesenchymal stem cells support acute myeloid leukaemia cells and promote therapy resistance

Abstract

The bone marrow (BM) is the primary site of adult haematopoiesis, where stromal elements (e.g. fibroblasts and mesenchymal stem cells [MSCs]) work in concert to support blood cell development. However, the establishment of an abnormal clone can lead to a blood malignancy, such as acute myeloid leukaemia (AML). Despite our increased understanding of the pathophysiology of the disease, patient survival remains suboptimal, mainly driven by the development of therapy resistance. In this review, we highlight the importance of bone marrow fibroblasts and MSCs in health and acute myeloid leukaemia and their impact on patient prognosis. We discuss how stromal elements reduce the killing effects of therapies via a combination of contactdependent (e.g. integrins) and contact-independent (i.e. secreted factors) mechanisms, accompanied by the establishment of an immunosuppressive microenvironment. Importantly, we underline the challenges of therapeutically targeting the bone marrow stroma to improve acute myeloid leukaemia patient outcomes, due to the inherent heterogeneity of stromal cell populations.

GDF11 level and its effect on prognosis in patients with acute myeloid leukemia

“…HSC self-renewal and differentiation are controlled by the surrounding bone marrow microenvironment. 34 Disruption of signaling between HSCs and the bone marrow microenvironment that regulates cell proliferation and differentiation can lead to leukemia development. 34 Hamilton et al…”

“…34 Disruption of signaling between HSCs and the bone marrow microenvironment that regulates cell proliferation and differentiation can lead to leukemia development. 34 Hamilton et al…”

“…HSC self-renewal and differentiation are controlled by the surrounding bone marrow microenvironment. 34 Disruption of signaling between HSCs and the bone marrow microenvironment that regulates cell proliferation and differentiation can lead to leukemia development. 34 Hamilton et al showed that the TGFβ pathway was upregulated in stromal cells cultured with leukemia cells, and TGFβ inhibition decreased leukemic stem cells and increased apoptosis.…”

“…34 Disruption of signaling between HSCs and the bone marrow microenvironment that regulates cell proliferation and differentiation can lead to leukemia development. 34 Hamilton et al showed that the TGFβ pathway was upregulated in stromal cells cultured with leukemia cells, and TGFβ inhibition decreased leukemic stem cells and increased apoptosis. 35 In this study, inhibition of TGFβ signaling and decreased laminin expression resulted in impaired engraftment of leukemic cells into the bone marrow niche.…”

Cancer microenvironment and pharmacological interventions

“…Although research on MSCs/CAFs is highly encouraging, it is predominantly still at the preclinical phase, with no therapies targeting/modulating MSC/CAF function currently approved. Therapeutic intervention at the level of MSCs/CAFs has been hindered mainly due to the extensive diversity/heterogeneity of this cell population (Miari & Williams, 2023). Interestingly, an immunocytokine, Simlukafusp Alfa (FAP‐IL2v), a monoclonal antibody (mAb) targeting the CAF marker, fibroblast activation protein α (FAPα), conjugated to an IL‐2 variant (IL‐2v), has been tested in a recently completed Phase I clinical trial (NCT02627274) (Waldhauer et al, 2021).…”