Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Clonal evolution and intratumoral heterogeneity are key drivers of cancer progression.
• The underlying molecular mechanisms of these processes remain largely unknown.
• Understanding these mechanisms is crucial for developing effective cancer therapies.

Purpose of the Study:

• To investigate the functional differences and evolutionary dynamics of single T-cell acute lymphoblastic leukemia (T-ALL) clones.
• To identify molecular mechanisms underlying spontaneous clonal evolution in T-ALL.
• To assess the impact of clonal evolution on leukemia progression and drug resistance.

Main Methods:

• Utilized a zebrafish transgenic model to study single T-ALL clones.
• Assessed functional variations, growth rates, and leukemia-propagating potential over time.
• Analyzed molecular pathways, including Akt and mTORC1 signaling, and Myc protein stability.
• Evaluated drug resistance to dexamethasone and the effect of Akt inhibition.

Main Results:

• Observed significant functional variation within individual T-ALL clones.
• Identified a subset of clones that enhanced growth rate and leukemia-propagating potential over time.
• Found acquired Akt pathway activation in evolved clones, leading to increased leukemia-propagating cells via mTORC1 activation.
• Demonstrated that Akt activation stabilized Myc, elevated growth rate, and conferred dexamethasone resistance.
• Showed that combined treatment with an Akt inhibitor reversed dexamethasone resistance.

Conclusions:

• T-ALL clones exhibit spontaneous and continuous evolution, driving leukemia progression independently of therapy-induced selection.
• Akt pathway activation is a critical mechanism acquired during clonal evolution, promoting T-ALL progression.
• Targeting the Akt pathway offers a potential therapeutic strategy to overcome drug resistance in T-ALL.