Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms

Area of Science:

• Hematology
• Molecular Biology
• Cancer Biology

Background:

• Janus kinases (JAKs) are crucial for cellular signaling, and JAK2 mutations drive myeloproliferative neoplasms (MPNs).
• Current JAK inhibitors show limited efficacy in eradicating JAK2-mutated clones, necessitating research into disease persistence mechanisms.

Purpose of the Study:

• To investigate the molecular mechanisms underlying the persistence of JAK2-mutated clones despite JAK inhibitor treatment.
• To identify novel therapeutic targets that can enhance the efficacy of JAK inhibitors in MPNs.

Main Methods:

• In-depth phosphoproteome profiling to identify targets of mutant JAK2.
• Functional studies involving YBX1 inactivation and JAK inhibition in JAK2-mutated cells and animal models.
• Analysis of RNA splicing, transcriptional control, and extracellular signal-regulated kinase (ERK) signaling.

Main Results:

• Proteins involved in mRNA processing, including YBX1, were identified as targets of mutant JAK2.
• Inactivation of YBX1 sensitized persistent cells to apoptosis and caused RNA mis-splicing and disrupted ERK signaling.
• Combined JAK inhibition and YBX1 inactivation led to apoptosis, malignant clone regression, and molecular remission in vivo.

Conclusions:

• Differential protein phosphorylation of YBX1 by mutant JAK2 contributes to splicing-dependent alterations in JAK2-ERK signaling, maintaining malignant clones.
• Targeting YBX1-dependent ERK signaling in combination with JAK2 inhibition offers a potential strategy for eradicating JAK2-mutated cells.