JAK2 inhibition mediates clonal selection of RAS pathway mutations in myeloproliferative neoplasms

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Janus Kinase (JAK) inhibitors, including ruxolitinib, have been used for a decade to treat myeloproliferative neoplasms (MPN).
• Understanding the long-term effects of JAK inhibitors on MPN clonal evolution is crucial for optimizing patient outcomes.

Purpose of the Study:

• To investigate the impact of ruxolitinib treatment on the clonal evolution of myelofibrosis (MF).
• To determine the relationship between RAS pathway mutations and patient survival during JAK inhibitor therapy.

Main Methods:

• Longitudinal molecular evaluation of a myelofibrosis patient cohort.
• Single-cell DNA sequencing and ex vivo treatment of CD34+ cells with RAS mutations.
• In vitro and in vivo competition assays to assess cellular fitness.

Main Results:

• Ruxolitinib treatment is associated with the clonal outgrowth of RAS pathway mutations in MPN patients.
• Ruxolitinib induces RAS clonal selection in both JAK/STAT wild-type and hyper-activated contexts.
• RAS mutations correlate with decreased transformation-free and overall survival specifically in ruxolitinib-treated patients.
• RAS-mutated cells exhibit increased fitness under ruxolitinib or JAK2 knockdown, indicating an on-target effect.

Conclusions:

• JAK inhibitor therapy can lead to the selection and outgrowth of RAS mutations, potentially impacting patient survival.
• MAPK pathway activation, linked to JAK2 downregulation, enhances the oncogenic potential of RAS mutations.
• Pre-existing RAS mutations should be screened in MPN patients considered for JAK inhibitor treatment.