pexidartinib and Lymphoma--T-Cell--Peripheral

Peripheral T-cell lymphomas are clinically aggressive and usually fatal, as few complete or durable remissions are achieved with currently available therapies. Recent evidence supports a critical role for lymphoma-associated macrophages during T-cell lymphoma progression, but the specific signals involved in the cross-talk between malignant T cells and their microenvironment are poorly understood. Colony-stimulator factor 1 receptor (CSF1R, CD115) is required for the homeostatic survival of tissue-resident macrophages. Interestingly, its aberrant expression has been reported in a subset of tumors. In this article, we evaluated its expression and oncogenic role in T-cell lymphomas.. Loss-of-function studies, including pharmacologic inhibition with a clinically available tyrosine kinase inhibitor, pexidartinib, were performed in multiple. We observed that CSF1R is aberrantly expressed in many T-cell lymphomas, including a significant number of peripheral and cutaneous T-cell lymphomas. Colony-stimulating factor 1 (CSF1), in an autocrine or paracrine-dependent manner, leads to CSF1R autophosphorylation and activation in malignant T cells. Furthermore, CSF1R signaling was associated with significant changes in gene expression and in the phosphoproteome, implicating PI3K/AKT/mTOR in CSF1R-mediated T-cell lymphoma growth. We also demonstrated that inhibition of CSF1R. Collectively, these findings implicate CSF1R in T-cell lymphomagenesis and have significant therapeutic implications.

Topics: Aminopyridines; Animals; Cell Line, Tumor; Gene Expression Profiling; Humans; Lymphoma, T-Cell, Peripheral; Macrophage Colony-Stimulating Factor; Macrophages; Mice; Mice, Inbred NOD; Mice, SCID; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrroles; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Microenvironment; Xenograft Model Antitumor Assays