Targeting TYK2: A Novel Therapeutic Vulnerability in CALR-Mutant Myeloproliferative Neoplasms

Highlight

• CALR-mutant myeloproliferative neoplasms (MPNs) exhibit constitutive activation of TYK2 signaling, distinct from JAK2V617F-driven MPNs where TYK2 is dispensable.
• Selective TYK2 inhibition with deucravacitinib reduces cell viability and STAT3/5 phosphorylation in CALR-mutant and MPL-mutant cells but not in JAK2V617F-mutant cells.
• Combined TYK2 and JAK2 inhibition enhances therapeutic efficacy, overcoming resistance associated with JAK2 protein abundance variability.
• Primary patient samples and patient-derived iPSC models confirm the selective dependency of CALR-mutant MPNs on TYK2 signaling, supporting clinical translation.