MARIMO cells harbor a CALR mutation but are not dependent on JAK2/STAT5 signaling

Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants

“…10 Another type 1 mutant, del61 CALR, reported in the MARIMO cell line, 30 derived from an ET patient who was treated with Busulfan, 43 also activates TpoR (supplemental Figure 2A-B). Mutants that preserve stretches of negativelycharged residues like ins5 do not show calcium defects.…”

“…Constitutive activation of MAPK and PI3-K pathways was also seen by luciferase assay with pSRE and 6xDBE (supplemental Figure 2B-C). Interestingly, CALR mutant 30 found in the MARIMO cell line and exhibiting the same 21/12 frameshift was also capable of activating STAT5 and MAPK (supplemental Figure 2A-B).…”

Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms

“…Furthermore, there is evidence that CALR mutations are also associated with increased JAK-STAT signaling, 38,40 although some studies have suggested that other pathways may be of more importance. 41 CALR is not known to have a direct role in cytokine signaling, hematopoiesis or cell fate decisions, and therefore the mechanism(s) by which CALR mutations result in megakaryocytic proliferation and an ET/MF phenotype were not initially apparent. CALR is known to be involved in the regulation of calcium uptake and release in the endoplasmic reticulum, 42 and acts as a chaperone, together with calnexin and ERp57, to form part of the regulatory machinery involved in the folding and quality control of newly synthesized glycoproteins.…”

The JAK-STAT signaling pathway is differentially activated in CALR-positive compared with JAK2V617F-positive ET patients

“…4 However, these data contrast with the observation that MARIMO cells, derived from an ET patient harboring an endogenous CALR mutation, contain very low levels of tyrosine-phosphorylated and unphosphorylated JAK2 and STAT5, and are insensitive to JAK2 inhibition. 5 Rampal et al subsequently reported in this journal that a gene expression signature of JAK2 activation is shared by peripheral blood granulocytes from JAK2-mutant and CALR-mutant MPN patients. 6 Microarray gene expression data for 93 MPN patients and 11 age-matched controls were described, providing a valuable resource for the MPN field.…”