Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia.

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• High hyperdiploidy (HD) is the most common subtype of B-cell acute lymphoblastic leukemia (B-ALL).
• While largely curable, significant treatment-related morbidity necessitates research into HD-ALL biology and novel drug targets.
• Identifying novel driver genes is crucial for improving therapeutic strategies and reducing patient burden.

Purpose of the Study:

• To identify novel driver genes in HD-ALL by performing targeted deep-sequencing.
• To investigate the landscape of mutations in epigenetic regulatory genes and the RTK/Ras/MAPK signaling pathway.
• To explore the extent of tumor heterogeneity and its implications in HD-ALL.

Main Methods:

• Targeted deep-sequencing of 538 cancer-relevant genes was performed in 57 HD-ALL patients.
• Patients selected lacked overt KRAS/NRAS hotspot mutations and common B-ALL deletions to focus discovery on novel drivers.
• Analysis included assessment of mutations in epigenetic regulators, RTK/Ras/MAPK pathway genes, and tumor heterogeneity.

Main Results:

• One-third of patients had damaging mutations in epigenetic regulatory genes, including DOT1L (n=4).
• Two-thirds of patients showed mutations in the RTK/Ras/MAPK pathway, including novel ROS1 mutations.
• Significant co-occurrence of FLT3 and DOT1L mutations (p=0.04) was observed, suggesting functional cooperation.
• Extraordinary tumor heterogeneity was detected, with microclonal hotspot mutations (KRAS, NRAS, FLT3, PTPN11) in 54.4% of patients.
• Multiple KRAS/NRAS microclonal mutations co-occurred significantly (p=4.8x10-4), indicating ongoing Ras-activating mutation selection.

Conclusions:

• HD-ALL harbors novel driver mutations in epigenetic and RTK/Ras/MAPK pathways.
• The presence of tumor heterogeneity and microclonal mutations suggests complex leukemogenesis and potential for therapeutic resistance.
• Further investigation into tumor microheterogeneity and epigenetic dysregulation may reveal novel therapeutic approaches for HD-ALL.