Mixed phenotype acute leukemia contains heterogeneous genetic mutations by next-generation sequencing

Area of Science:

• Hematology
• Oncology
• Genetics

Background:

• Mixed phenotype acute leukemia (MPAL) is a rare and complex hematological malignancy.
• Accurate classification and understanding of MPAL's genetic underpinnings are crucial for effective treatment strategies.

Purpose of the Study:

• To characterize the genetic landscape of de novo MPAL cases using next-generation sequencing (NGS).
• To correlate genetic findings with immunophenotype (B-cell/myeloid, T-cell/myeloid) and cytogenetic abnormalities.
• To evaluate the prognostic significance of genetic mutations and immunophenotype on overall survival.

Main Methods:

• Analysis of 14 de novo MPAL cases meeting 2016 WHO classification criteria.
• Next-generation sequencing (NGS) using gene panels of varying sizes (28, 53, or 81 genes).
• Karyotype analysis was performed in conjunction with NGS.

Main Results:

• 25 distinct mutations in 15 genes were identified in 64% of patients; FLT3-ITD was the only recurrent mutation.
• T-cell/myeloid (T/My) MPAL cases showed a higher mutation rate (100%) compared to B-cell/myeloid (B/My) cases (43%).
• B/My MPAL cases more frequently exhibited complex karyotypes (71%) than T/My MPAL cases (17%).
• Combined NGS and karyotype analysis revealed abnormalities in 93% of MPAL cases.
• No significant difference in overall survival was observed between B/My and T/My MPAL, or between mutated and non-mutated MPAL cases.

Conclusions:

• The genetic landscape of MPAL is diverse, with most cases harboring mutations or cytogenetic abnormalities.
• Immunophenotypic differences between B/My and T/My MPAL may reflect distinct leukemogenesis pathways.
• Further research into immunophenotype-specific mechanisms is warranted for improved MPAL management.