ULK1 inhibition promotes oxidative stress-induced differentiation and sensitizes leukemic stem cells to targeted...

Area of Science:

• Oncology
• Molecular Biology
• Cellular Biology

Background:

• Autophagy inhibition is a potential cancer therapy, but current inhibitors show limited clinical efficacy.
• Minimal residual disease in chronic myeloid leukemia (CML) is driven by resistant leukemic stem cells (LSCs).
• Novel, specific autophagy inhibitors require validation in preclinical models for CML therapy.

Purpose of the Study:

• To investigate the role of autophagy-inducing kinase ULK1 in CML.
• To evaluate ULK1 inhibition as a therapeutic strategy against CML LSCs.
• To explore the mechanisms underlying ULK1 inhibition-induced CML LSC targeting.

Main Methods:

• Deletion of ULK1 in CML cell lines and patient-derived xenografts in mouse models.
• Pharmacological inhibition of ULK1 in primitive CML cells ex vivo and in vivo.
• Combination therapy of ULK1 inhibitors with tyrosine kinase inhibitors (TKIs).
• Analysis of mitochondrial respiration, quiescence, and oxidative stress in CML LSCs.

Main Results:

• ULK1 deletion reduced the growth of CML cells in preclinical models.
• Pharmacological ULK1 inhibition selectively targeted CML LSCs when combined with TKIs.
• ULK1 inhibition enhanced TKI sensitivity by increasing mitochondrial respiration and reducing quiescence.
• This led to oxidative stress-induced differentiation of CML LSCs.

Conclusions:

• ULK1 is a critical target for eliminating CML LSCs.
• Combined ULK1 inhibition and TKI treatment represents a promising therapeutic strategy for CML.
• Targeting ULK1-mediated autophagy offers an alternative approach to overcome TKI resistance in CML.