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1.
J Neurooncol ; 168(2): 317-332, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38630384

ABSTRACT

INTRODUCTION: Patients with pediatric low-grade gliomas (pLGGs), the most common primary brain tumors in children, can often benefit from MAPK inhibitor (MAPKi) treatment. However, rapid tumor regrowth, also referred to as rebound growth, may occur once treatment is stopped, constituting a significant clinical challenge. METHODS: Four patient-derived pediatric glioma models were investigated to model rebound growth in vitro based on viable cell counts in response to MAPKi treatment and withdrawal. A multi-omics dataset (RNA sequencing and LC-MS/MS based phospho-/proteomics) was generated to investigate possible rebound-driving mechanisms. Following in vitro validation, putative rebound-driving mechanisms were validated in vivo using the BT-40 orthotopic xenograft model. RESULTS: Of the tested models, only a BRAFV600E-driven model (BT-40, with additional CDKN2A/Bdel) showed rebound growth upon MAPKi withdrawal. Using this model, we identified a rapid reactivation of the MAPK pathway upon MAPKi withdrawal in vitro, also confirmed in vivo. Furthermore, transient overactivation of key MAPK molecules at transcriptional (e.g. FOS) and phosphorylation (e.g. pMEK) levels, was observed in vitro. Additionally, we detected increased expression and secretion of cytokines (CCL2, CX3CL1, CXCL10 and CCL7) upon MAPKi treatment, maintained during early withdrawal. While increased cytokine expression did not have tumor cell intrinsic effects, presence of these cytokines in conditioned media led to increased attraction of microglia cells in vitro. CONCLUSION: Taken together, these data indicate rapid MAPK reactivation upon MAPKi withdrawal as a tumor cell intrinsic rebound-driving mechanism. Furthermore, increased secretion of microglia-recruiting cytokines may play a role in treatment response and rebound growth upon withdrawal, warranting further evaluation.


Subject(s)
Brain Neoplasms , Cytokines , Glioma , Microglia , Mutation , Protein Kinase Inhibitors , Proto-Oncogene Proteins B-raf , Humans , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Microglia/metabolism , Microglia/drug effects , Glioma/metabolism , Glioma/drug therapy , Glioma/pathology , Glioma/genetics , Cytokines/metabolism , Animals , Brain Neoplasms/metabolism , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Brain Neoplasms/genetics , Protein Kinase Inhibitors/pharmacology , Xenograft Model Antitumor Assays , Child , Mice , Cell Proliferation/drug effects , Cell Line, Tumor , MAP Kinase Signaling System/drug effects
2.
Leukemia ; 37(7): 1474-1484, 2023 07.
Article in English | MEDLINE | ID: mdl-37161070

ABSTRACT

The persistence of leukemic stem cells (LSCs) represents a problem in the therapy of chronic myeloid leukemia (CML). Hence, it is of utmost importance to explore the underlying mechanisms to develop new therapeutic approaches to cure CML. Using the genetically engineered ScltTA/TRE-BCR::ABL1 mouse model for chronic phase CML, we previously demonstrated that the loss of the docking protein GAB2 counteracts the infiltration of mast cells (MCs) in the bone marrow (BM) of BCR::ABL1 positive mice. Here, we show for the first time that BCR::ABL1 drives the cytokine independent expansion of BM derived MCs and sensitizes them for FcεRI triggered degranulation. Importantly, we demonstrate that genetic mast cell deficiency conferred by the Cpa3Cre allele prevents BCR::ABL1 induced splenomegaly and impairs the production of pro-inflammatory cytokines. Furthermore, we show in CML patients that splenomegaly is associated with high BM MC counts and that upregulation of pro-inflammatory cytokines in patient serum samples correlates with tryptase levels. Finally, MC-associated transcripts were elevated in human CML BM samples. Thus, our study identifies MCs as essential contributors to disease progression and suggests considering them as an additional target in CML therapy. Mast cells play a key role in the pro-inflammatory tumor microenvironment of the bone marrow. Shown is a cartoon summarizing our results from the mouse model. BCR::ABL1 transformed MCs, as part of the malignant clone, are essential for the elevation of pro-inflammatory cytokines, known to be important in disease initiation and progression.


Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Leukemia, Myeloid , Humans , Mice , Animals , Mast Cells/metabolism , Splenomegaly/etiology , Splenomegaly/prevention & control , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/metabolism , Cytokines , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Disease Models, Animal , Protein Kinase Inhibitors/therapeutic use , Tumor Microenvironment
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