Coexistence of JAK2 and CALR mutations and their clinical implications in patients with essential thrombocythemia.

Min-Gu Kang,Yong Jun Choi,Hyun-Jung Choi,Myung-Geun Shin,Michael Szardenings,Soon-Pal Suh,Jun Hyung Lee,Hye-Ran Kim,Hyun-Woo Choi,Jong-Hee Shin

doi:10.18632/oncotarget.10958

Abstract

Janus kinase 2 (JAK2) and calreticulin (CALR) constitute the two most frequent mutations in essential thrombocythemia (ET), and both are reported to be mutually exclusive. Hence, we examined a cohort of 123 myeloproliferative neoplasm (MPN) patients without BCR-ABL1 rearrangement and additional ET patients (n=96) for coexistence of JAK2 and CALR mutations. The frequency of CALR mutations was 20.3% in 123 MPN patients; 31.1% in ET (n=74), 25% in primary myelofibrosis (n=4) and 2.2% in polycythemia vera (n=45). JAK2 and CALR mutations coexisted in 7 (4.2%) of 167 ET patients. Clinical characteristics, progression-free survival (PFS), and elapsed time to achieve partial remission across 4 groups (JAK2+/CALR+, JAK2+/CALR-, JAK2-/CALR+, JAK2-/CALR-) were reviewed. The JAK2+/CALR- group had higher leukocyte counts and hemoglobin levels and more frequent thrombotic events than JAK2-/CALR- group. JAK2 mutations have a greater effect on the disease phenotype and the clinical features of MPN patients rather than do CALR mutation. JAK2+ groups showed a tendency of poor PFS than JAK2- groups regardless of CALR mutation. CALR+ was a predictor of late response to the treatment. Our study also showed that thrombosis was more frequent in ET patients with type 2 CALR mutations than in those with type 1 CALR mutations.

Highlights

Myeloproliferative neoplasms (MPNs) are clonal diseases of hematopoietic stem cells
The discovery of CALR mutations further assists the diagnosis of BCRABL1 rearrangement-negative MPNs, and it is thought that CALR mutations will eventually be included in the essential thrombocythemia (ET) and primary myelofibrosis (PMF) diagnostic criteria of the World Health Organization (WHO) [11]
A CALR exon 9 mutation was observed in a polycythemia vera (PV) patient who was negative for Janus kinase 2 (JAK2) mutations; this mutation was only observed in the fragment analysis and not via direct sequencing

Summary

Introduction

Myeloproliferative neoplasms (MPNs) are clonal diseases of hematopoietic stem cells. MPNs usually exhibit terminal myeloid cell expansion in the peripheral blood [1]. BCR-ABL1 rearrangement-negative MPNs can be classified as polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis (PMF). The discovery of JAK2 mutations has been a great help in the diagnosis of BCR-ABL1 rearrangement-negative MPNs. Subsequent studies identified a thrombopoietin receptor (MPL) exon 10 mutation in 3–5% of ET patients and 5–8% of PMF patients without JAK2 mutations [4,5,6]. In 2008, the World Health Organization (WHO) designated JAK2 and MPL mutations as MPN diagnostic criteria [7, 8]. The discovery of CALR mutations further assists the diagnosis of BCRABL1 rearrangement-negative MPNs, and it is thought that CALR mutations will eventually be included in the ET and PMF diagnostic criteria of the WHO [11]

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