Arellano Abstract Type A P&F 2025

Abstract: Myeloproliferative disorders (MPDs) are a group of hematopoietic diseases that result in the excess production of mature myeloid cells. Mutations in the gene encoding calreticulin (CALR) represent the second most common mutation in these diseases. There are currently no targeted treatments for CALR mutant MPDs, underscoring the need for identifying new treatment strategies. To this end, we aim to better understand the molecular etiology of CALR mutant MPD cells. We previously showed that the most common CALR mutation, CALRdel52, results in a loss of calcium (Ca2+) binding function and subsequently elevated cytosolic Ca2+ levels, and this phenotype can be rescued with a CALR Ca2+ binding rescue construct (P+C) [1]. We have also found that in parallel with increased cytosolic Ca2+ levels, CALRdel52 cells have an increased glycolytic capacity and derive the majority of their ATP from glycolysis. Intriguingly, restoring Ca2+ homeostasis with the P+C construct can ameliorate this glycolytic phenotype. To reveal how wildtype CALR is regulated by metabolism and how CALR mutants may escape this regulation, we will use mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically (MIDAS), part of the Center for Iron and Heme Disorders (CIHD) Protein-Metabolite Discovery core, a novel method of detecting protein-metabolite ligand interactions [2].
Ultimately, this work will shed light on the metabolic mechanism(s) that regulate CALR and how CALRdel52 mutations reprogram cellular metabolism to drive MPDs.