Targeting mesenchymal stromal cells for the treatment of acute myeloid leukemia
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Abstract
Acute myeloid leukemia (AML) is characterized by the uncontrolled proliferation of immature myeloid cells, leading to suppression of normal hematopoiesis. Treatment strategies for AML are complex and include conventional chemotherapy, targeted therapies, immunotherapy, and allogeneic hematopoietic stem cell transplantation (alloHSCT). Despite these advances, the prognosis for many AML patients remains poor, largely due to disease relapse. One of the major contributing factors is the supportive role of the bone marrow microenvironment, where stromal cells can create a protective “safe haven” for residual AML blasts.
Non-hematopoietic stromal cells within the bone marrow play an essential role in promoting AML cell survival, proliferation, immune evasion, and relapse after therapy. Therefore, disrupting tumor-stroma crosstalk through pharmacological intervention represents a promising therapeutic strategy that could complement existing chemotherapy or immunotherapy approaches.
Bone marrow is a highly specialized tissue composed of diverse cellular populations. In this study, our primary focus was on mesenchymal stromal cells (MSCs) and their interactions with AML cells. We hypothesized that AML cells promote a tumor-supportive microenvironment by reprogramming MSCs and altering their functional properties, and that these processes may be regulated by the p38α signalling pathway. Specifically, we aimed to evaluate the impact of p38α inhibition in MSCs on key stroma-dependent AML functions, including leukemic cell proliferation, susceptibility to cytotoxic T-cell-mediated killing, and sensitivity to chemotherapy. The overall objective was to identify novel druggable targets in MSCs that could support the development of combination therapies for AML.
Our findings demonstrated that p38α acts as a central regulator of the pro-tumorigenic functions of MSCs by controlling their inflammatory responses, secretory profile, differentiation potential toward adipogenesis and fibrosis, and reprogramming into a cancer-associated phenotype. Inhibition of the p38α pathway and its associated targets, including UNC5B, IL7Rα, IL17D, and HAS2, disrupted this regulatory network, resulting in MSC reprogramming and reduced support for AML blasts. Pharmacological compounds targeting the p38α pathway and its newly identified downstream targets suppressed AML growth, increased AML cells' sensitivity to the chemotherapeutic agents doxorubicin and venetoclax, delayed AML relapse, and enhanced cytotoxic T cell activation in vitro. Mice with genetically inactivated p38α (Mapk14) showed significantly increased survival in an AML model.
As therapeutic strategies targeting the tumor microenvironment gain increasing importance, these findings provide a foundation for future studies exploring stroma-targeted combination therapies. Ultimately, such approaches have a strong potential to improve treatment outcomes for patients with AML.
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This item has been published with the following license: In Copyright