Calreticulin mutation does not contribute to disease progression in essential thrombocythemia by inhibiting phagocytosis.

Abstract:

:Somatic mutations of calreticulin (CALR) have been observed in many cases of essential thrombocythemia (ET) or primary myelofibrosis that harbor non-mutated Janus kinase 2 (JAK2). CALR mainly localizes within the endoplasmic reticulum lumen, but a small fraction of the total CALR pool is distributed over the cell surface. Cell surface CALR is known to transduce prophagocytic "eat me" signals to macrophages and acts as one of the important regulators for macrophage engulfment. In this study, we attempted to clarify whether mutant CALR may affect the threshold for macrophage engulfment and play an integral role in the pathogenesis of CALR-mutated ET. First, we compared the surface expression levels of CALR on hematopoietic stem and progenitor cells (HSPCs) and mature blood cells in patients with myeloproliferative neoplasms and found that the surface expression of mutant CALR did not change. Next, we compared the threshold for macrophage phagocytosis of each HSPC fraction and mature blood cells and found no significant change in the efficiency of macrophage engulfment. Our data suggest that CALR mutation does not affect sensitivity to phagocytosis by macrophages. Finally, we analyzed the phosphorylation statuses of molecules downstream of JAK2 at each HSPC level in patients with ET and found that CALR mutations activated the JAK-STAT pathway in a manner similar to that associated with JAK2 mutations. These results indicate that mutant CALR causes myeloproliferation because of the activation of JAK-STAT pathway and not by the inhibition of phagocytosis, which is similar to the myeloproliferation caused by JAK2 V617F mutation.

journal_name

Exp Hematol

journal_title

Experimental hematology

authors

Daitoku S,Takenaka K,Yamauchi T,Yurino A,Jinnouchi F,Nunomura T,Eto T,Kamimura T,Higuchi M,Harada N,Saito N,Miyamoto T,Iwasaki H,Akashi K

doi

10.1016/j.exphem.2016.05.001

subject

Has Abstract

pub_date

2016-09-01 00:00:00

pages

817-825.e3

issue

9

eissn

0301-472X

issn

1873-2399

pii

S0301-472X(16)30126-6

journal_volume

44

pub_type

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