Pediatric T-ALL type-1 and type-2 relapses develop along distinct pathways of clonal evolution

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• T-cell acute lymphoblastic leukemia (T-ALL) relapse mechanisms are poorly understood.
• Identifying distinct relapse pathways is crucial for improving patient outcomes.

Purpose of the Study:

• To elucidate the molecular mechanisms differentiating T-ALL relapse types.
• To investigate the clonal origins and genetic drivers of relapse in T-ALL.

Main Methods:

• Multilevel-omics analysis of 38 matched initial and relapsed T-ALL patient samples.
• Comparative analysis of type-1 (major ancestral clone) and type-2 (minor ancestral clone) relapses.
• Deconvolution analysis of ATAC-Seq profiles to assess T-ALL cellular composition.

Main Results:

• Identified 18 type-1 and 20 type-2 relapses, with distinct genetic and epigenetic profiles.
• Both relapse types share multidrug resistance drivers (MDR1, MVP, NT5C2, JAK-STAT).
• Type-1 relapses show IL7R upregulation; type-2 relapses exhibit cancer predisposition gene mutations, divergent remodeling, and hypermutator phenotypes (BLM, BUB1B/PMS2, TP53).
• Type-2 relapses originate from complex subclonal architectures present at initial diagnosis.
• ATAC-Seq deconvolution revealed distinct cellular origins for type-1 (immature thymic T-cells) and type-2 (mixed T-cell precursors) relapses.

Conclusions:

• Fundamentally different mechanisms drive type-1 and type-2 T-ALL relapse.
• The capacity for disease evolution is inherent in the initial leukemia's molecular setup.
• Distinct relapse pathways suggest the need for tailored therapeutic strategies based on relapse type.