Alterations of Signaling Pathways in Essential Thrombocythemia with Calreticulin Mutation

Abstract

Purpose

Though mutations of the calreticulin (CALR) gene have been identified in essential thrombocythemia patients, the detailed mechanisms for CALR mutations have not been completely clarified. Our study is aimed at characterizing alteration of protein expression in ET patients with mutated CALR^del52 and further recognizing possible involvement of signaling pathways associated with CALR mutations.

Patients and Methods

Protein pathway array was performed to analyze the expression levels of proteins involved in various signaling pathways in peripheral blood neutrophils from 18 ET patients with mutated CALR^del52, 20 ET patients with JAK2^V617F mutation and 20 controls.

Results

We found 20 proteins differentially expressed in ET patients with mutated CALR^del52 compared with healthy controls. These proteins were associated with molecular mechanisms of cancer in ingenuity pathways analysis (IPA) network. We identified top ten canonical pathways which including apoptotic pathways and cellular cytokine pathways might participate in pathogenesis of ET with mutated CALR^del52. Additionally, there were 8 proteins found to be dysregulated differently between ET patients with mutated CALR^del52 and those with JAK2^V617F mutation. These proteins might be related to the unique signaling pathways activated by CALR^del52 mutation which were different to JAK/STATs pathway by JAK2^V617F mutation.

Conclusion

Our study demonstrated that numerous alterations of signaling proteins and pathways in ET patients with mutated CALR^del52. These findings could help to gain insights into the pathological mechanisms of ET.

Keywords:

• essential thrombocytosis
• CALR^del52 mutation
• protein pathway array
• signaling proteins

Acknowledgments

We thank Dr. David Y. Zhang and Dr. Fei Ye (Mount Sinai Hospital) for the technical support in PPA experiments.

Disclosure

Dr Wuhan Hui reports grants from National Natural Science Foundation of China grants (grant nos. 81400094), during the conduct of the study. The authors report no conflicts of interest in this work. The partial abstract of this paper was presented at the ASH Conference name “Alterations of Signaling Pathways in Essential Thrombocythemia with Calreticulin Mutation” as a poster presentation. The poster’s abstract was published in “Poster Abstracts” in Blood Journal: https://doi.org/10.1182/blood.V128.22.4286.4286