Order-of-Mutation Effects on Cancer Progression: Models for Myeloproliferative Neoplasm.

Area of Science:

• Genetics and Molecular Biology
• Computational Biology and Bioinformatics
• Hematology and Oncology

Background:

• Myeloproliferative neoplasms (MPN) frequently exhibit co-occurring JAK2 V617F and TET2 mutations.
• The sequence of mutation acquisition can influence gene expression, disease progression, and patient prognosis in MPN.

Purpose of the Study:

• To develop a mathematical framework explaining the non-additive and non-commutative effects of JAK2 V617F and TET2 mutations in MPN.
• To investigate the role of gene expression bistability in mediating order-of-mutation effects observed in MPN.

Main Methods:

• Utilized nonlinear ordinary differential equations and Markov chain models to simulate mutation dynamics.
• Integrated clinical observations of gene expression patterns, mutation allele frequencies, and age at diagnosis into the modeling framework.

Main Results:

• The proposed models successfully explain observed clinical data, including gene expression patterns and patient ages at diagnosis.
• Bistability in gene expression is identified as a key mechanism underlying the observed order-of-mutation effects in MPN.

Conclusions:

• The order of JAK2 V617F and TET2 mutation acquisition significantly impacts MPN pathogenesis and clinical outcomes.
• Gene expression bistability offers a parsimonious explanation for these order-dependent mutation effects, providing a basis for future experimental validation.