Abstract
Primary myelofibrosis (PMF) is a type of myeloproliferative neoplasm (MPN) that is typically caused by hyperactive JAK-STAT signaling due to mutations in JAK2, CALR, or MPL. We identified two patients exhibiting features of MF on bone marrow biopsy due to an activating mutation in calcium sensor STIM1, a known cause of the rare congenital disorder Stormorken syndrome (SS), though fibrosis had not been previously described. We aimed to further uncover the distinct relationship between dysregulated STIM1 activity and the development of MF in SS and how it may be related in MPNs. Our two patients with activating mutations in STIM1 (R304W and S88G) experience dysregulation of the store operated calcium entry system (SOCE) in all cells, but within the bone marrow (BM) they exhibit this dysfunction with marked reticulin fibrosis and megakaryocytic hyperplasia and atypia. While the relationship between calcium signaling and BM fibrosis is previously unstudied, it is well established that MF is frequently caused by and related to inflammatory signaling within the BM niche. Single cell RNA-sequencing (scRNA-seq) verified that both patients demonstrated elevated NFκB inflammatory signaling in peripheral blood (PB) monocyte populations, suggesting a link between altered SOCE activity and aberrant inflammation, and an interface between inducing MF development. To corroborate our findings from these patients, we generated a novel knock-in mouse model of the heterozygous Stim1 R304W mutation as seen in many SS patients. When induced by the universal driver CMV-Cre, we recapitulated multiple SS features as seen in patients, including thrombocytopenia, tubular aggregate myopathy, growth deficiency, and the development of BM fibrosis. To focus on the hematopoietic features of SS, we induced the R304W mutation in hematopoietic cells specifically via Vav-Cre, again recapitulating thrombocytopenia and MF development, with mice developing splenomegaly, a common feature of MPNs, as young as 9 weeks old. Bone marrow cytokine analysis of these mice did find elevated expression of inflammatory cytokines IL-1α and Il-1β, along with others. To explore what role SOCE plays in the development of MPNs, we queried bulk RNA-sequencing (RNA-seq) of hematopoietic stem/progenitor cells (HSPC) cells from patients with MPNs, as well as megakaryocyte progenitors and platelets, and found that STIM1 mRNA was upregulated in all populations in MPN patient samples. To test if this was a potential therapeutic target, we generated patient derived xenograft (PDX) models with CALR- and JAK2-mutant patient samples with CRISPR ablation of STIM1. In multiple CALR-mutant experiments, we found that abrogation of STIM1 led to a mild decrease in disease burden in mice compared to unedited CALR-mutant mice. This was contrasted in mice with STIM1-targeted CRISPR in JAK2-mutant mice, where the exacerbation of disease phenotypes such as splenomegaly, led to significantly earlier lethality. Altogether, we have demonstrated a novel role of aberrant SOCE-induced inflammation underlying the development of MF in SS, a finding previously not described in the literature. We also identified unique interactions between SOCE and JAK2- and CALR-driven MPNs, with potential implications for the development of targeted therapeutic approaches for both disorders.
Committee Chair
Stephen Oh
Committee Members
Grant Challen; Jorge Di Paola; Regina Clemens; Robert Campbell; Stephen Sykes
Degree
Doctor of Philosophy (PhD)
Author's Department
Biology & Biomedical Sciences (Cancer Biology)
Document Type
Dissertation
Date of Award
8-7-2026
Language
English (en)
DOI
https://doi.org/10.7936/tvev-km86
Recommended Citation
Brakhane, Molly, "Aberrant Activity of the Calcium Sensor STIM1 Drives Thrombocytopenia and Bone Marrow Fibrosis in Stormorken Syndrome" (2026). Arts & Sciences Graduate Student Theses and Dissertations. 3832.
The definitive version is available at https://doi.org/10.7936/tvev-km86