ABL1 and ABL2 promote medulloblastoma leptomeningeal dissemination

Abstract

Background Medulloblastoma is the most common malignant pediatric brain tumor, and leptomeningeal dissemination (LMD) of medulloblastoma both portends a poorer prognosis at diagnosis and is incurable at recurrence. The biological mechanisms underlying LMD are unclear. The Abelson (ABL) tyrosine kinase family members, ABL1 and ABL2, have been implicated in cancer cell migration, invasion, adhesion, metastasis, and chemotherapy resistance, and are upstream mediators of the oncogene c-MYC in fibroblasts and lung cancer cells. However, their role in medulloblastoma has not yet been explored. The purpose of this work was to elucidate the role of ABL1/2 in medulloblastoma LMD. Methods ABL1 and ABL2 mRNA expression of patient specimens was analyzed. shRNA knockdowns of ABL1/2 and pharmacologic inhibition of ABL1/2 were used for in vitro and in vivo analyses of medulloblastoma LMD. RNA sequencing of ABL1/2 genetic knockdown versus scrambled control medulloblastoma was completed. Results ABL1/2 mRNA is highly expressed in human medulloblastoma and pharmacologic inhibition of ABL kinases resulted in cytotoxicity. Knockdown of ABL1/2 resulted in decreased adhesion of medulloblastoma cells to the extracellular matrix protein, vitronectin (P = .0013), and significantly decreased tumor burden in a mouse model of medulloblastoma LMD with improved overall survival (P = .0044). Furthermore, both pharmacologic inhibition of ABL1/2 and ABL1/2 knockdown resulted in decreased expression of c-MYC, identifying a putative signaling pathway, and genes/pathways related to oncogenesis and neurodevelopment were differentially expressed between ABL1/2 knockdown and control medulloblastoma cells. Conclusions ABL1 and ABL2 have potential roles in medulloblastoma LMD upstream of c-MYC expression.

Elucidating cellular response to treatment with viral immunotherapies in pediatric high-grade glioma and medulloblastoma

“…RNA sequencing was completed as previously described [25] for D283, D324, D341, and D556 medulloblastoma and D456 and X21584 pHGG for the following G207 treatment conditions: control (0 h), 8 h after viral infection, 24 h after viral infection. RNA sequencing was completed for D283, D324, D341, and D556 medulloblastoma for the following PVSRIPO treatment conditions: control (0 h), 8 h after viral infection, 24 h after viral infection.…”

Overcoming Treatment Resistance in Medulloblastoma: Underlying Mechanisms and Potential Strategies

“…Similarly, epigenetic regulation of MYC through pharmacological and genetic inactivation of the upstream Ableson tyrosine kinase (ABL1/2) results in decreased C-MYC expression and tumor progression. ABL inhibition also downregulates the epithelial mesenchymal transition (EMT) to restrict leptomeningeal dissemination of tumor cells [ 105 ]. Protein arginine methyltransferase 5 (PRMT5) has also been recognized as an epigenetic promoter and stabilizer of MYC in various cancers [ 106 ].…”

Tumor Dormancy and Reactivation: The Role of Heat Shock Proteins

“…Trombetta-Lima and colleagues, who conducted the study, noted an increase in the dense fibrillary ECM proteins fibrillins and lumicans in medulloblastoma, which were not observed in GBM aside from collagen, that was seen in both tumors [266]. Additionally, recurrent medulloblastomas show increased leptomeningeal dissemination (LMD), dependent on vitronectin-ABL (Abelson) kinase binding that polymerizes actin filaments for c-Myc expression [267].…”