Journal
EMBO REPORTS
Volume 23, Issue 4, Pages -Publisher
WILEY
DOI: 10.15252/embr.202152904
Keywords
calreticulin; monoclonal antibody; myelofibrosis; myeloproliferative neoplasm; stem cell progenitor
Categories
Funding
- National Health and Medical Research Council [APP1182564, APP 2004288]
- Australian Cancer Research Foundation (ACRF) Cancer Genomics Facility
- ACRF Discovery Accelerator
- Commonwealth Serum Laboratories Centenary Fellowship
- Leukemia & Lymphoma Society Translational Research Program
- Australian Medical Research Future Fund for Rare Diseases, Rare Cancers and Unmet Need
- Austrian Science Fund [P32783, I5021]
- Austrian Society of Internal Medicine (Joseph-Skoda Award)
- Austrian Society of Haematology and Medical Oncology (Clinical Research Grant)
- MEFOgraz
- Hospital Research Fund
- Detmold Hoopman Group, ACRF
- Australian Government
- Austrian Science Fund (FWF) [I5021, P32783] Funding Source: Austrian Science Fund (FWF)
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Researchers have developed a specific antibody, 4D7, that can selectively target common CALR mutations, inhibiting the proliferation and megakaryocyte differentiation of mutant CALR myelofibrosis progenitors and providing a novel therapeutic approach.
Calreticulin (CALR) is recurrently mutated in myelofibrosis via a frameshift that removes an endoplasmic reticulum retention signal, creating a neoepitope potentially targetable by immunotherapeutic approaches. We developed a specific rat monoclonal IgG2 alpha antibody, 4D7, directed against the common sequence encoded by both insertion and deletion mutations. 4D7 selectively bound to cells co-expressing mutant CALR and thrombopoietin receptor (TpoR) and blocked JAK-STAT signalling, TPO-independent proliferation and megakaryocyte differentiation of mutant CALR myelofibrosis progenitors by disrupting the binding of CALR dimers to TpoR. Importantly, 4D7 inhibited proliferation of patient samples with both insertion and deletion CALR mutations but not JAK2 V617F and prolonged survival in xenografted bone marrow models of mutant CALR-dependent myeloproliferation. Together, our data demonstrate a novel therapeutic approach to target a problematic disease driven by a recurrent somatic mutation that would normally be considered undruggable.
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