Microenvironmental CXCL12 deletion enhances Flt3-ITD acute myeloid leukemia stem cell response to therapy by reducing p38 MAPK signaling

Comparison of Quantitative Mass Spectrometric Methods for Drug Target Identification by Thermal Proteome Profiling

“…The activation of the p38 MAPK pathway plays a critical role in orchestrating a range of cellular stresses, growth, and survival of tumor cells. , p38 MAPK is often increased and/or overactivated in AML blasts and represents an important pharmacological target. − However, selective p38 MAPK inhibitors have limited efficacy and for a variety of clinical indications none have progressed to Phase III . Losmapimod (known as GW856553 or GSK-AHAB) is a selective, potent, and orally MAPK14 (p38α MAPK) ATP competitive inhibitor used in several clinical trials (Table S1).…”

Pharmacological p38 MAPK inhibitor SB203580 enhances AML stem cell line KG1a chemosensitivity to daunorubicin by promoting late apoptosis, cell growth arrest in S-phase, and miR-328-3p upregulation

“…Here, an enhancement of KG1a cell sensitivity to DNR was revealed by an augmented apoptosis induction visualized by flow cytometry after blocking p38 MAPK using the pharmacological inhibitor SB203580, which was greater than our previous study using SB202190 combined with 5-Fluorouridine ( Matou-Nasri et al, 2022 ). Additionally, using in vitro and fms-like tyrosine kinase 3 (Flt3)-internal tandem duplication (ITD) and Ten-eleven-translocation 2 (Tet2)-deleted AML genetic mouse models, p38 signaling inhibition in AML cells reduced mesenchymal stem cells-maintained AML chemoresistance potential, which enhanced their sensitivity to the chemotherapy ( Anderson et al, 2023 ). In addition, In this study, the apoptotic status was confirmed by the detection of apoptosis-related protein markers, such as apoptosis executioner cleaved caspase-3, intrinsic pathway-related cleaved caspase-9, and cleaved PARP for oligonucleosomal DNA fragmentation, and visualized by increased caspase-3/-7 and mPTP activities.…”

The relevance of the hematopoietic niche for therapy resistance in acute myeloid leukemia

“…Survival of AML cells was decreased by CXCR4 inhibition in combination with venetoclax by affecting antiapoptotic proteins and the transcription program of stemness genes (Figure 2A). Similarly, the response of CXCR4‐expressing LSCs to chemotherapy and TKIs was improved by CXCR12 inhibition or depletion in FLT3‐ITD mutated AML 52 . In co‐culture experiments with MSCs, downstream activation of p38 MAPK and ERK supported AML cell proliferation and protection.…”