Molecular-defined clonal evolution in patients with classical myeloproliferative neoplasms

Area of Science:

• Hematology
• Molecular Biology
• Genetics

Background:

• Classical myeloproliferative neoplasms (MPNs) exhibit diverse clinical features.
• Driver mutations in JAK2, CALR, and MPL genes have elucidated MPN pathogenesis.
• Next-generation sequencing (NGS) has identified additional somatic mutations, particularly in epigenetic modulator genes.

Purpose of the Study:

• To genetically characterize a cohort of 95 MPN patients using targeted NGS.
• To analyze mutation acquisition and clonal hierarchies via single-cell derived colony-forming progenitor assays.
• To evaluate the hierarchy of mutations within distinct cell lineages.

Main Methods:

• Targeted next-generation sequencing (NGS) for genetic characterization of 95 MPN patients.
• Colony-forming progenitor assays using single cells to study mutation acquisition and clonal hierarchies.
• Evaluation of mutation hierarchy within specific myeloid and lymphoid cell lineages.

Main Results:

• NGS identified mutations in TET2, DNMT3A, and ASXL1 as frequent co-mutations with classical MPN driver mutations.
• JAK2^V617F, DNMT3A, and TET2 mutations were identified as early events in MPN formation, often following a linear mutation pattern.
• Mutations were predominantly observed in myeloid lineages but also detected in lymphoid subpopulations, with one MPL-mutated case showing exclusive monocyte lineage involvement.

Conclusions:

• This study confirms the significant mutational heterogeneity in classical MPNs.
• JAK2^V617F and epigenetic modifier gene mutations play crucial roles as early events in the development of these hematologic malignancies.