Effect of CALR and JAK2 mutations on the clinical and hematological phenotypes of the disease in patients with myelofibrosis – long-term experience from a single center

Abstract

Primary myelofibrosis (PMF) is a chronic clonal myeloid disorder. Together with essential thrombocythemia (ET) and polycythemia vera (PV), it belongs to a group of Philadelphia chromosome-negative myeloproliferative neoplasms. An integral part of laboratory tests carried out in this disease group is detecting the presence of mutations in the Janus kinase 2 gene at position 617 (JAK2 V617F) and in the gene encoding for the receptor for thrombopoietin (myeloproliferative leukemia virus oncogene, MPL) found in approximately 60% of PMF patients. The discovery of mutations affecting exon 9 of the calreticulin (CALR) gene was of great benefit to the diagnosis of the diseases in JAK2 V617F and MPL unmutated cases. This is a study of the effect of a mutation in the CALR gene on the clinical course in patients with primary, post-ET and post-PV myelofibrosis. Analysis of 66 patients (54.5% JAK2 V617F; 34.8% CALR; 6.1% MPL; 3.0% triple negative; 1.5% coincidence of CALR and JAK2 V617F) confirmed a different phenotype of the disease in CALR-mutated patients as compared with CALR-unmutated individuals. Those with CALR mutation were significantly younger and had borderline higher platelet counts, less pronounced splenomegaly and less frequent B symptoms at diagnosis. The study suggests that the driver mutation types define variations in the biological basis, clinical manifestations and course of the disease. The presence of CALR mutation has been shown to be an independent prognostic favorable factor. Careful risk stratification of these patients is of great importance to adequate therapeutic decision-making and aids in selecting high-risk patients eligible for allogeneic hematopoietic stem cell transplantation which continues to be the only treatment modality for myelofibrosis having curative potential.

Neutrophil-specific expression of JAK2-V617F or CALRmut induces distinct inflammatory profiles in myeloproliferative neoplasia

“…On the contrary, upregulation of pro-inflammatory cytokines was almost absent in serum of Ly6G-Cre CALR +/del mice. This is in line with the clinical observation of less frequent inflammatory symptoms of CALR mutated MPN patients [ 26 ]. Differential expression of TNFα protein in primary hematopoietic cell populations isolated from JAK2-V617F versus CALR mutant patients has also been described by Fisher and colleagues [ 88 ].…”

“…Interestingly, previous work has demonstrated that neutrophils and monocytes moving along and adhering to the endothelium provide the initiating stimulus for thrombosis development [ 101 – 103 ]. Hence, the observed differences in migration and adhesion between JAK2-V617F and CALRdel positive neutrophils aligns with the clinical observation that JAK2-V617F is the primary driving force of the pro-thrombotic risk in MPN whereas mutated CALR seems to have a lesser impact [ 26 , 27 ].…”

“…However, according to a recent meta-analysis in PMF, CALR-mutated patients demonstrated a lower risk of thrombosis than JAK2-mutated patients [ 25 ]. In myelofibrosis, CALR-mutated patients also displayed a distinct disease phenotype compared to JAK2-V617 positive individuals: CALR mutated patients presented with less frequent inflammatory symptoms upon diagnosis, fewer thrombotic complications and less prominent splenomegaly [ 26 ]. A similar genotype-phenotype correlation is evident in ET: CALR mutated individuals are substantially different from JAK2-V617F positive patients in terms of hematologic and clinical features [ 27 ].…”

The Role of Navitoclax in Myelofibrosis

“…Mutations in the MPL lead to increased JAK/STAT activation, leading to downstream effects of changes in cytokines and growth factors that promote fibrosis. Mutations in the calreticulin gene (CALR) have also been seen in patients with PMF promoting similar downstream activation of the JAK/STAT pathway [ 10 - 11 ]. Overall, 90% of patients with PMF have the JAK2, MPL, or CALR mutation, which are mutually exclusive [ 12 ].…”