CBP/catenin antagonist safely eliminates drug-resistant leukemia-initiating cells

Area of Science:

• Molecular Biology
• Cancer Research
• Hematology

Background:

• CREB-binding protein (CBP) and p300 are homologous transcriptional coactivators.
• CBP and p300 bind various proteins, including catenins-β and γ.
• ICG-001 is a specific inhibitor of the CBP/catenin interaction, not p300/catenin.

Purpose of the Study:

• To investigate the therapeutic potential of specifically inhibiting the CBP/catenin interaction using ICG-001.
• To determine if ICG-001 can sensitize drug-resistant chronic myelogenous leukemia-initiating cells (CML LICs) to tyrosine kinase inhibitors.
• To evaluate the efficacy of ICG-001 in eliminating CML LICs in a preclinical mouse model.

Main Methods:

• Utilizing ICG-001 to specifically inhibit the CBP/catenin interaction.
• Treating quiescent, drug-resistant CML LICs to induce differentiation.
• Administering ICG-001 in combination with BCR-ABL tyrosine kinase inhibitors (e.g., Imatinib).
• Employing a NOD/SCID/IL2Rγ(-/-) mouse model engrafted with human CML.

Main Results:

• Specific inhibition of CBP/catenin interaction with ICG-001 induced differentiation of CML LICs.
• ICG-001 sensitized CML LICs to tyrosine kinase inhibitors like Imatinib.
• Combination therapy with ICG-001 led to complete elimination of engrafted human CML in mice.
• Treated animals showed no adverse effects on endogenous hematopoietic stem cells and survived as long as controls.

Conclusions:

• Targeting the CBP/catenin interaction with ICG-001 is a viable strategy for eliminating drug-resistant CML LICs.
• Combination therapy involving ICG-001 can eradicate CML without compromising normal stem cell function.
• ICG-001 offers a promising therapeutic approach for overcoming drug resistance in chronic myelogenous leukemia.