Orphan drug development for targeting chronic myeloid leukemia stem cells

ABSTRACT

Introduction: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disease that derives from an abnormal hematopoietic stem cell (HSC) harboring the Philadelphia (Ph⁺) chromosome. Tyrosine kinase inhibitors (TKIs) successfully target BCR-ABL oncoprotein, and block the cellular proliferation and survival, thereby dramatically increase the long-term survival rates of the majority of CML patients in chronic phase. However, TKIs are unable to deplete leukemia stem cells, which are responsible for the relapse of CML patients. Therefore, in CML biology, the limitations of TKIs require us to seek effective strategy to target leukemia stem cells (LSCs).

Areas covered: This review first summarizes the characterization of CML and the features of several tyrosine kinase inhibitors, which are currently in use in clinics. We further discuss leukemia stem cells and focus on the new potential target-PPARγ and its function in eradicating LSCs of CML.

Expert opinion: Because of the inability of TKIs to target CML LSCs, the current major goal in CML biology is to explore an effective strategy to target LSCs. Combining an agent targeting LSC with TKIs might be the right direction in the future. PPARγ is essential for regulating the survival of LSCs, and combination of PPARγ agonists with TKIs effectively depletes LSCs, providing a promising strategy for curing CML. However, the function of PPARγ agonists should be further assessed in clinical trials, and side effects should be carefully evaluated.

KEYWORDS:

• Chronic myeloid leukemia
• BCR-ABL
• leukemia stem cell
• tyrosine kinase inhibitors
• PPARγ agonist

Article highlights

• Chronic myeloid leukemia (CML) is a clonal myeloproliferative disease that derives from an abnormal hematopoietic stem cell transformed by the protein-tyrosine kinase BCR-ABL.

• Inhibition of BCR-ABL kinase with tyrosine kinase inhibitors (TKIs) has revolutionized disease management.

• Leukemia stem cells (LSCs) are responsible for the relapse of CML due to the resistance to tyrosine kinase inhibitors.

• PPARγ acts as a potential target for eradicating TKI-resistance CML stem cells.

• Combining an agent targeting LSC with TKIs might represent a right direction for CML treatment in the future.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.