Ultraprecision therapy for type 1 vs type 2 CALR+ MPN by dual epitope targeting that restores ruxolitinib sensitivity

Thompson-Peach, CAL; Panagopoulos, RA; Thomas, D; Hercus, TR; Dottore, M; Wardill, HR; Lim, K; Kamel, MM; Stomski, F; Nair, PC; Fo&#223;elteder, J; Reinisch, A; Chandrakanthan, V; Jenkner, S; Bland, L; Paton, S; Gronthos, S; Kan, WL; Moretti, PA; Pitson, SM; Burbury, K; Ross, DM; Lopez, AF; Tvorogov, D

Author(s): Thompson-Peach, CAL; Panagopoulos, RA; Thomas, D; Hercus, TR; Dottore, M; Wardill, HR; Lim, K; Kamel, MM; Stomski, F; Nair, PC; Foßelteder, J; Reinisch, A; Chandrakanthan, V; Jenkner, S; Bland, L; Paton, S; Gronthos, S; Kan, WL; Moretti, PA; Pitson, SM; Burbury, K; Ross, DM; Lopez, AF; Tvorogov, D;
Details: Publication Year 2026-04-02,Volume 147,Issue #14,Page 1611-1623
Journal Title: Blood
Publication Type: Research article
Abstract: Somatic frameshift mutations in the gene encoding calreticulin (CALR) give rise to myelofibrosis and are classified as type 1 (del52) or type 2 (ins5) according to the degree of wild-type sequence retained adjacent to the neopeptide, with each type conferring different clinical outcomes. Targeting strategies specific for type 1 vs type 2 mutations would have enormous clinical utility in the treatment and prevention of myelofibrosis as responses to tyrosine kinase inhibitors are not durable nor mutation specific. Here, we show that dual targeting of type 1 (del52) mutant CALR with 2 monoclonal antibodies directed against distinct epitopes in CALR have significant advantages compared with single-agent treatment in the eradication of primary megakaryocyte progenitors in vitro and in a humanized ossicle microenvironment leading to improved survival in xenograft models. Dual targeting was superior in blocking constitutive STAT5 and extracellular signal-regulated kinase phosphorylation induced by del52 and prevented accumulation of Janus kinase 2 (JAK2) phosphorylation, overcoming ruxolitinib resistance. In contrast, type 2 mutations showed increased CALR dimerization and were partially resistant to antibody targeting but could be affected by a ruxolitinib triple combination. Together, our data demonstrate an ultraprecision medicine approach tailored to either type 1 or type 2 mutation classes will be required for maximal efficacy and complete blockade of JAK/STAT signaling, with far-reaching implications for patient management.
Publisher: American Society of Hematology
Keywords: Nitriles; Pyrimidines; Humans; *Pyrazoles/pharmacology/therapeutic use; *Calreticulin/genetics/immunology; Animals; Mice; *Epitopes/immunology; *Primary Myelofibrosis/drug therapy/genetics; Janus Kinase 2/metabolism; *Antibodies, Monoclonal/pharmacology/therapeutic use; Frameshift Mutation; Drug Resistance, Neoplasm/drug effects; Xenograft Model Antitumor Assays
Department(s): Haematology
Publisher's Version: https://doi.org/10.1182/blood.2024027897
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-01-23 05:48:33

Last Modified: 2026-04-14 03:18:24