Multifaceted mechanisms for cell survival and drug targeting in chronic myelogenous leukemia

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Tyrosine kinase inhibitors (TKIs) like imatinib, nilotinib, and dasatinib have significantly improved outcomes for chronic myelogenous leukemia (CML) by targeting the BCR-ABL1 tyrosine kinase.
• Despite TKI advancements, a complete cure for CML remains elusive, as leukemia cells develop resistance through various survival mechanisms.

Purpose of the Study:

• To review the multifaceted mechanisms, both BCR-ABL1-dependent and -independent, that enable CML cells to survive and resist TKI treatment.
• To identify key survival pathways and propose novel therapeutic strategies for the complete eradication of residual CML cells.

Main Methods:

• Literature review of current knowledge on CML cell survival and resistance mechanisms.
• Analysis of BCR-ABL1-mediated and -independent pathways contributing to CML cell protection.
• Synthesis of information on intrinsic and extrinsic molecular mechanisms of resistance.

Main Results:

• CML cells employ diverse protective strategies against TKIs, including overlapping signaling pathways, BCL2 family modulation, autophagy, bone marrow microenvironment support, and genetic instability.
• These mechanisms contribute to the persistence of CML cells, hindering a complete cure with current TKI therapies.
• BCR-ABL1-independent kinase activities also play a role in CML cell survival.

Conclusions:

• A comprehensive understanding of CML cell resistance mechanisms is essential for developing more effective treatments.
• Future therapeutic strategies should aim to overcome these multifaceted survival pathways to achieve complete CML cell elimination and potentially a cure.
• Targeting residual CML cells during TKI treatment is critical for long-term disease control.