Preclinical study identifies PERK signaling vulnerability in CALR-mutated myeloproliferative neoplasms

Researchers investigated disease-initiating hematopoietic stem cells (HSCs) in calreticulin (CALR)-mutated myeloproliferative neoplasms using CALRdel52 and CALRins5 knock-in mice crossed with Vwf-promoter GFP reporter mice. This approach distinguished platelet-biased, Vwf-positive HSCs from other subsets. The study also included reanalysis of a previous patient hematopoietic stem and progenitor cell (HSPC) dataset and pharmacological experiments in patient-derived cells. Sample sizes were not reported in the available abstract.

Disease initiation was mainly associated with expansion of Vwf-positive HSCs, without substantially changing their lineage bias. Greater amplification of CALRdel52 than CALRins5 HSCs was associated with increased thrombopoietin receptor MPL signaling and activation of the PERK/eIF2a integrated stress response pathway. Patient CALRdel52-like HSPCs also showed transcriptional upregulation of this pathway and increased eIF2a phosphorylation compared with CALRins5-like cells.

Pharmacological PERK inhibition reduced proliferation of mouse CALRdel52 HSCs and impaired megakaryocytic differentiation of patient CALRdel52-like HSPCs while sparing healthy-donor cells. These findings provide a mechanistic rationale for further investigation, not evidence of clinical benefit or safety. The abstract provides no numerical effect estimates, and the full text was unavailable for assessment.