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Updated: Jan 22, 2026
Isolation of the Side Population in Myc-induced T-cell Acute Lymphoblastic Leukemia in Zebrafish
Published on: May 4, 2017
Novel synthetic tosyl chloride-berbamine regresses lethal MYC-positive leukemia by targeting CaMKIIγ/Myc axis
Qingfeng Yu1, Ping Wang1, Linlin Yang1
1Department of Hematology and Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
Abstract:
Proto-oncogene Myc, a key transcription factor, is frequently deregulated in human leukemia with aggressive and poor clinical outcome, but the development of MYC inhibitors remains challenging due to MYC helix-loop-helix topology lacking druggable domains. Here we describe a novel oral active small molecule analog of berbamine, tosyl chloride-berbamine (TCB), that efficiently eliminates MYC-positive leukemia in vitro and in vivo. Mechanistically, TCB potently reduced MYC protein by inhibiting CaMKIIγ, a critical enzyme that stabilizes MYC protein, and induces apoptosis of MYC-positive leukemia cells. In vivo, oral administration of TCB markedly eliminated lethal MYC-positive acute lymphoblastic leukemia (ALL) with well tolerability in orthotopic mouse model. Our studies identify CaMKIIγ/Myc axis as a valid target for developing small molecule-based new therapies for treating MYC-mediated leukemia and demonstrate that TCB is an orally active analog of berbamine that kills MYC-positive leukemia cells.
Insights
A novel small molecule, tosyl chloride-berbamine (TCB), effectively eliminates MYC-positive leukemia by inhibiting CaMKIIγ, a key enzyme stabilizing MYC protein. This orally active compound shows promise for treating aggressive leukemia.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Proto-oncogene Myc deregulation is common in aggressive human leukemia, leading to poor clinical outcomes.
- Developing MYC inhibitors is difficult due to the protein's structural features, lacking accessible drug-binding sites.
Purpose of the Study:
- To identify and evaluate a novel small molecule inhibitor targeting MYC-positive leukemia.
- To investigate the mechanism of action and in vivo efficacy of the novel compound.
Main Methods:
- Synthesis and characterization of tosyl chloride-berbamine (TCB), a berbamine analog.
- In vitro assessment of TCB's effect on MYC protein levels and leukemia cell apoptosis.
- In vivo evaluation of TCB's efficacy and tolerability in a mouse model of acute lymphoblastic leukemia (ALL).
Main Results:
- TCB significantly reduced MYC protein levels by inhibiting CaMKIIγ, an enzyme crucial for MYC stabilization.
- TCB induced apoptosis in MYC-positive leukemia cells in vitro.
- Oral administration of TCB effectively eliminated lethal MYC-positive ALL in vivo with good tolerability.
Conclusions:
- The CaMKIIγ/Myc axis represents a viable therapeutic target for MYC-mediated leukemias.
- TCB is a potent, orally active small molecule that demonstrates efficacy against MYC-positive leukemia, offering a potential new treatment strategy.
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