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Updated: Jun 24, 2026
Isolation, Enrichment, and Maintenance of Medulloblastoma Stem Cells
Published on: September 1, 2010
ABL1 and ABL2 promote medulloblastoma leptomeningeal dissemination
Jill K Jones1,2, Hengshan Zhang2, Anne-Marie Lyne3,4,5
1Harvard/MIT MD-PhD Program, Boston, MA, USA.
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.
Insights
Abelson (ABL) kinases ABL1 and ABL2 are highly expressed in pediatric medulloblastoma and drive leptomeningeal dissemination (LMD). Inhibiting ABL1/2 decreases tumor growth and improves survival by reducing cell adhesion and c-MYC expression.
Area of Science:
- Pediatric neuro-oncology
- Molecular mechanisms of cancer metastasis
- Tyrosine kinase signaling pathways
Background:
- Medulloblastoma is the most common malignant pediatric brain tumor.
- Leptomeningeal dissemination (LMD) in medulloblastoma is associated with poor prognosis and is difficult to treat.
- The role of Abelson (ABL) tyrosine kinases (ABL1/2) in medulloblastoma LMD is unexplored.
Purpose of the Study:
- To investigate the role of ABL1 and ABL2 in medulloblastoma leptomeningeal dissemination (LMD).
- To determine if ABL1/2 are potential therapeutic targets for medulloblastoma LMD.
Main Methods:
- Analysis of ABL1 and ABL2 mRNA expression in patient medulloblastoma specimens.
- In vitro and in vivo studies using shRNA knockdown and pharmacologic inhibition of ABL1/2.
- RNA sequencing to identify downstream molecular pathways affected by ABL1/2 inhibition.
Main Results:
- ABL1/2 mRNA expression is significantly elevated in human medulloblastoma.
- Pharmacologic inhibition of ABL kinases induces medulloblastoma cell cytotoxicity.
- ABL1/2 knockdown reduces medulloblastoma cell adhesion to vitronectin, decreases tumor burden in vivo, and improves overall survival in a mouse model of LMD.
- ABL1/2 inhibition or knockdown leads to decreased c-MYC expression, suggesting a role in a specific signaling pathway.
- Differential gene expression analysis reveals alterations in oncogenesis and neurodevelopment pathways following ABL1/2 knockdown.
Conclusions:
- ABL1 and ABL2 are highly expressed in medulloblastoma and play a role in leptomeningeal dissemination (LMD).
- Targeting ABL1/2 may represent a novel therapeutic strategy for medulloblastoma LMD.
- ABL1/2 may exert their effects upstream of c-MYC expression in medulloblastoma LMD.
