Targeting quiescent leukemic stem cells using second generation autophagy inhibitors

Area of Science:

• Hematology
• Cancer Biology
• Molecular Medicine

Background:

• Tyrosine kinase inhibitor (TKI) treatment for chronic myeloid leukemia (CML) can induce autophagy, promoting leukemic stem cell (LSC) survival and TKI resistance.
• The clinically approved autophagy inhibitor hydroxychloroquine (HCQ) shows inconsistent efficacy in cancer patients, necessitating more potent alternatives.

Purpose of the Study:

• To investigate the efficacy of novel autophagy inhibitors, Lys05 and PIK-III, in targeting LSCs in a murine model of CML.
• To evaluate the combination therapy of autophagy inhibitors with TKIs for improved CML treatment outcomes.

Main Methods:

• Generation of a murine CML model for measuring autophagic flux in LSCs.
• Utilizing cell division tracing, phenotyping, and xenotransplantation models to assess Lys05 and PIK-III effects on LSCs.
• Comparing basal autophagy levels in leukemic versus non-leukemic long-term hematopoietic stem cells (LT-HSCs).

Main Results:

• Leukemic LT-HSCs exhibit higher basal autophagy than non-leukemic LT-HSCs and more mature leukemic cells.
• Lys05 effectively inhibited autophagy, reduced LSC quiescence, and promoted myeloid cell expansion, unlike HCQ.
• Combination therapy with Lys05 or PIK-III and TKI significantly reduced primary and xenografted CML LSC numbers.

Conclusions:

• Lys05 and PIK-III are potent autophagy inhibitors effective against CML LSCs.
• Second-generation autophagy inhibitors offer a promising therapeutic strategy for CML patients with persistent LSCs, especially when combined with TKIs.