Selective dependency of CALR-mutant myeloproliferative neoplasms on TYK2 signaling

Myeloproliferative neoplasms (MPN) are driven by the oncoproteins JAK2V617F, mutant calreticulin (CALR), and mutant thrombopoietin receptor (TPOR), all of which activate JAK/STAT signaling. While JAK2 signaling is engaged in all MPNs, TYK2 is dispensable for JAK2V617F-driven disease. Here, we hypothesized a distinct role for TYK2 in CALR-mutant driven MPN. We found constitutive TYK2 phosphorylation in CALRdel52/ins5- and MPLW515K- but not JAK2V617F-expressing cells. Modelling of JAK2/TPOR vs. TYK2/TPOR interaction confirmed similar binding affinities of both kinases to the receptor, which was more relevant in CALRdel52-positive cells. The TYK2 inhibitor deucravacitinib reduced viability and STAT3/5 phosphorylation in CALRdel52/ins5- and MPLW515K- but not JAK2V617F-mutant cells, with enhanced efficacy when combined with the JAK2-selective inhibitor fedratinib. Cellular response correlated with JAK2 protein abundance, as CALRins5 JAK2 ^high clones outcompeted JAK2 ^low clones upon TYK2 inhibition. In primary samples, deucravacitinib significantly suppressed colony growth in ET and PMF but not PV, and selectively reduced CALR- but not JAK2V617F-mutant allele burden. Similarly, CALR-mutant patient-specific iPSC-derived CD34 ⁺ progenitors were more sensitive to TYK2 inhibition than their JAK2V617F counterparts. These findings identify TYK2 as a selective vulnerability in CALR-mutant MPN and support combined TYK2/JAK2 inhibition strategies to overcome JAK2-dependent resistance.