Characterization of disease-initiating hematopoietic stem cells in calreticulin-mutated myeloproliferative neoplasms.

CALR-mutated myeloproliferative neoplasms originate mainly from expansion of Vwf-positive, platelet-biased hematopoietic stem cells, with CALRdel52 mutations showing greater amplification.

• Why it matters: Understanding the specific HSC subset responsible for disease initiation is crucial for developing targeted therapies and improving patient outcomes in MPNs driven by CALR mutations.
• What they did: Researchers used mouse models with CALR mutations crossed with GFP reporter mice to identify HSC subsets, analyzing signaling pathways and transcriptional profiles, including patient data reanalysis.
• The result: The study reveals that the PERK/eIF2a pathway is a key vulnerability in CALR-mutated HSCs, and its inhibition reduces proliferation and differentiation, suggesting new therapeutic strategies.