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The role of calreticulin mutations in myeloproliferative neoplasms


Unique frameshift mutations in the calreticulin (CALR) gene, which encodes an endoplasmic reticulum (ER)-localized molecular chaperone, have been identified in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF), which are subgroups of myeloproliferative neoplasms (MPNs). In this review, we discuss the current understanding of the consequences of these mutations with regard to tumorigenesis and/or signal transduction. Expression of mutant CALR induces thrombocytosis in animal models, producing the phenotype of ET. Mutant CALR preferentially interacts with and activates the thrombopoietin receptor MPL, resulting in MPL-dependent cellular transformation. A novel carboxyl-terminal sequence generated by a frameshift mutation in CALR mediates intermolecular interactions to form homomultimers and induces structural changes required for MPL binding and activation. The homomultimerized mutant CALR behaves similarly to a cytokine, stabilizing homodimerized MPL by binding to immature MPL N-glycans. Mutant CALR may engage with MPL in the ER, but fails to dissociate, conveying MPL to the cell surface where MPL activation is likely to occur. Collectively, cell-autonomous and constitutive activation of MPL is a cause of MPNs that are mediated by mutant CALR. Novel therapeutic strategies for treating MPNs that target these mechanisms should, therefore, be developed.


The pathogenesis of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), which include three major disease subgroups: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), has been clarified following the identification of underlying recurrent somatic mutations and the functional characterization of the genes containing these mutations. A V617F mutation was first identified on a gene encoding janus kinase 2 (JAK2) in patients with MPN in 2005 [1,2,3,4]. Soon after, myeloproliferative leukemia protein (MPL) W515K/L [5, 6] and JAK2 exon 12 [7] mutations were identified in ET and PMF, and PV patients, respectively. Functional characterization of these mutant genes defined them as driver mutations for MPN [8], implying that activation of the MPL-JAK2 axis is a cause of MPN, and that activation of other receptor caused by the JAK2 mutation contributes to the diverse clinical features observed in MPNs. However, half of the patients with ET and PMF harbor neither JAK2 nor MPL mutations, and the pathogenesis of these “double-negative” patients remained undefined for a long time. After extensive investigation into the driver mutation in “double-negative” patients, a recurrent somatic mutation on calreticulin (CALR), which encodes an endoplasmic reticulum (ER)-resident molecular chaperone, was reported at the end of 2013 [9, 10]. Since then, studies have clarified the role of CALR mutations in the development of MPN and uncovered a novel molecular mechanism for the induction of cellular transformation.

Unique features of CALR mutations

CALR mutations found in MPN patients are usually frameshift mutations caused by a small deletion or insertion of nucleotides in exon 9, the final exon of CALR. To date, more than 50 different types of CALR mutations have been found, including a 52-base pair deletion (del52), called type 1, at a rate of approximately 50%, and a 5-base pair insertion (ins5), called type 2 at a rate of approximately 30% [10]. Based on the structural similarities of these two major mutant types, other CALR mutants have been grouped into type 1-like, type 2-like, and other types [11]. Unlike general frameshift mutations, which are scattered throughout a gene resulting in a loss-of-function, the frameshift mutations on CALR in MPN patients are accumulated in a narrow region, and the frameshift is always +1, suggesting that these are a gain-of-function mutation. Because of these unique features, all the mutant CALR in MPN patients shares amino acid sequences at their carboxyl(C)-terminal end (Fig. 1). This mutant-specific domain consists of a chain of positively charged amino acids, which replaces a cluster of negatively charged amino acids at the C-terminal end of wild-type (wt) CALR. Due to a lack of homology between this sequence and other reported proteins, the nature of the mutant-specific sequence has remained elusive until recently.

Fig. 1

Structural comparison of wild-type and mutant CALR. The domain structures of wild-type and mutant CALR adopted from reference [8]. CALR consists of the following domains: a signal peptide (SP), amino-terminal N-domain (N), proline-rich P-domain (P), and a carboxy-terminal C-domain (C), which includes an endoplasmic reticulum retention signal, KDEL, in the wild-type. Arrowheads indicate the boundary between the amino acid sequences unaffected and affected by the frameshift mutation. In wild-type CALR, the P-domain blocks binding of the N-domain to MPL. Mutant CALR loses a portion of the C-domain and gains a mutant-specific sequence common to all types of mutant CALR in MPNs. The domain with the mutant-specific sequence interacts with itself to form a homomultimeric complex, which induces a presumptive structural change, blocking the P-domain and enabling N-domain binding to MPL

Thrombocytosis is induced by mutant CALR in animal models

Animal models have been used to examine the causal role of mutant CALR in the development of MPN in vivo. Transduction of CALR del52 to lineage-negative [12] and c-KIT-enriched [13] cells, and subsequent transplantation to lethally irradiated mice resulted in an ET phenotype, with thrombocytosis associated with megakaryocyte hyperplasia and an expansion of hematopoietic stem cells in the bone marrow. Overexpression of CALR del52 by injection of mRNA in zebrafish embryos induced thrombocytosis [14]. Similar results were observed when CALR del52 was expressed with an H-2 Kb promoter in transgenic mice [15]. The expression of murine CALR (mCALR) where the C-terminal end was replaced with human CALR del52, with an endogenous promoter in conditional knock-in mice crossed with Mx-Cre and Vav1-Cre mice also exhibited thrombocytosis phenotype [16]. The thrombosis was observed in secondary transplanted mice [12, 16], implying that it is a cell-intrinsic phenomenon. In a competitive transplantation assay, CALR del52-expressing cells did not outcompete wild-type cells [15, 16], suggesting that additional factor(s) are involved in the development of MPN where CALR mutant dominance was observed. Bone marrow fibrosis was observed in transplanted mice long after engraftment [12], and in knock-in mCALR del52 homozygote mice [16]. These studies suggest that high levels of CALR del52 expression are required for the development of bone marrow fibrosis in mice.

In contrast to del52, the transduction of CALR ins5 does not confers the capacity for expansion to hematopoietic stem cells, and a bone marrow transplantation model exhibited mild thrombocytosis with no bone marrow fibrosis [12]. In zebrafish, overexpression of CALR ins5 failed to induce thrombocytosis [14]. Phenotypic differences between del52 and ins5 mutations are consistently observed between type 1-like mutants, such as del19, and type 2-like mutants, such as del34 and del36 [17]. The lack of bone marrow fibrosis phenotype in mice transplanted with type 2 and type 2-like-expressing cells may reflect the less frequently observed association between type 2 and type 2-like mutations with bone marrow fibrosis in humans [11]. However, bone marrow fibrosis is found in MPN patients harboring these mutations. In addition to this, a CRISPR-engineered mouse harboring a 19-base deletion on the murine CALR exon 9, which produces an mCALR similar to CALR del52, presented mild thrombocytosis [18]. Phenotypic differences between type 1 and 2 mutant CALR may be due to structural diversity: type 2 retains longer stretches of the negatively charged amino acids that originally existed in wt CALR than does type 1, which may neutralize the positive electronic charge generated by the clusters of positively charged amino acids in the mutant-specific sequence [11]. Nevertheless, further investigation is required to elucidate the cause of phenotypic differences between model animals and human cases.

MPL-dependent cellular transformation by mutant CALR

wt CALR is a multi-functional protein involved in calcium buffering, quality control of newly synthesized proteins in the ER, peptide loading onto the MHC class-I complex in the ER, and phagocytosis on the cell surface [19]. Due to a lack of evidence on the alteration of CALR in other malignancies and the involvement of wt CALR in signal transduction, the molecular mechanism linking MPN to mutant CALR was ambiguous. A series of in vitro studies uncovered a novel molecular mechanism of cellular transformation by the mutant chaperone. Transduction of CALR del52 and ins5 into cytokine-dependent cell lines revealed that the mutant CALR confers cytokine-independent growth in cells in a thrombopoietin receptor MPL-dependent manner, but not an erythropoietin or G-CSF receptor [12, 13, 20]. MPL-dependent and TPO-independent megakaryopoiesis caused by mutant CALR were demonstrated in murine lineage-negative cells [12], patient-derived CD34+ cells [21], and human iPS-derived hematopoietic progenitor cells [20, 22], demonstrating that MPL-dependent transformation by mutant CALR is a cause of megakaryocytosis in CALR-mutant MPN. The constitutive activation of MPL by mutant CALR resulted in the activation of JAK2 and its downstream molecules, including ERK1/2 and STAT5 [12, 13, 15, 20, 23, 24]. Taken together, this implies that the mutant CALR lies on the MPL-JAK2 axis in the development of MPN, and rationalizes the use of JAK inhibitors in CALR-mutant MPN patients.

Molecular mechanisms of MPL activation by mutant CALR

The observed functional interactions between mutant CALR and MPL led to further investigation into the physical interactions between these two molecules [13, 20, 21]. Although the mutant-specific sequence is required for MPL binding and activation [13, 25], the mutant-specific sequence does not serve as a binding domain for MPL. Instead, the amino (N)-terminal domain (N-domain) interacts with MPL [20]. This is consistent with the observation that the N-glycan binding motif of mutant CALR, which is located in the N-domain, is required for MPL activation [21] and the induction of MPL-dependent growth [26, 27]. These data seemingly contradict the fact that the N-domain in wt CALR has a very weak, if any, capacity to interact with MPL [13, 20, 21]. However, characterization of the MPL binding capacity of a series of truncated mutant CALRs revealed that the proline-rich (P) domain exerts an inhibitory effect on the N-domain in wt, but not mutant CALR, and that the mutant- specific sequence of the C-terminal end of mutant CALR blocks the P-domain, thus enabling strong binding of the N-domain to MPL (Fig. 1) [20].

The nature of the presumed structural changes induced by the mutant-specific sequence became clearer after the discovery that the mutant-specific sequence mediates intermolecular interactions between mutant CALR proteins to form a homomultimeric complex [25]. Interference caused by homomultimerization of mutant CALR attenuates MPL binding and activation, implying that the multimerization is a prerequisite for mutant CALR to interact with and activate MPL [25, 28]. The complex of homomultimerized mutant CALR and MPL was produced and purified as a recombinant protein, demonstrating the direct interaction between these molecules [29]. Furthermore, mutant CALR stabilized the dimerization of MPL in a JAK2-dependent manner [29], supporting a hypothetical model in which homomultimerized mutant CALR simultaneously interacts with dimerized MPL to activate oncogenesis [25, 28, 29].

The mode of interaction between mutant CALR and MPL is unique in the sense that the mutant CALR utilizes its capacity to interact with N-glycans, which is originally a feature of the N-domain of wt CALR. An N-glycan binding motif is required for mutant CALR to interact with and activate MPL [21, 26, 27, 29]. Concordantly, blocking N-glycosylation on asparagine 117 of MPL attenuated mutant CALR-dependent MPL activation [21, 26]. In the protein maturation process in the ER, wt CALR recognizes immature forms of N-glycans as a tag for immature proteins, then folds the tagged protein and dissociates from the target. In contrast, presumably due to a substantial structural change induced by the mutant-specific sequence, mutant CALR strongly interacts with immature N-glycans, but then fails to dissociate from immature MPL. In fact, the maturation of asparagine 117 on MPL bound by mutant CALR remains immature in insect cells [29], and an accumulation of immature MPL is observed in Ba/F3 cells expressing mutant CALR [21]. Besides asparagine 117, mutant CALR requires a hydrophobic patch located in the extracellular domain of MPL for activation [29]. Mutant CALR activates TPO binding-deficient MPL D261A/L265A [21]. These lines of evidence imply that the underlying mechanism of MPL activation by mutant CALR is distinctive from that of its natural ligand TPO.

Localization of MPL activation by mutant CALR

Because the interaction between mutant CALR and MPL depends on N-glycosylation of MPL, which takes place in the ER, the initial engagement between these proteins likely occurs in the ER. Blocking entrance to the ER by deleting the signal peptide on mutant CALR results in loss of MPL binding and oncogenicity [27, 29]. After mutant CALR binds to MPL in the ER, the complex moves to the plasma membrane through the Golgi apparatus (Fig. 2). Mutant CALR accumulates [20] and colocalizes with MPL on the cell surface [27, 29], and is even secreted out of cells [23](Fig. 2). Interestingly, mutant CALR is able to convey traffic-defective MPL R102P, which is found in patients with congenital amegakaryocytic thrombocytopenia, and MPL harboring an ER retention signal to the cell surface and induce activation there [29]. The capacity of mutant CALR to migrate towards the extracellular space is likely enhanced by the loss of the KDEL ER retention sequence at the carboxyl terminal of wt CALR, which is caused by the frameshift mutation in mutant CALR (Fig. 1).

Fig. 2

A model for the engagement between mutant CALR and MPL in a secretory pathway required for the activation of MPL on the cell surface. Homomultimerized mutant CALR recognizes immature N-glycans on MPL in the endoplasmic reticulum. The mutant CALR–MPL complex proceeds to the cell surface through the Golgi apparatus in the secretory pathway, due to the loss of the ER retention signal in mutant CALR (Fig. 1). Evidence strongly supports persistent activation of MPL by mutant CALR on the cell surface. Homomultimerized mutant CALR itself is also secreted out of cells

The location of MPL activation by mutant CALR is becoming clearer. Mutant CALR-dependent JAK2 activation is observed in the early endosome [29]. Persistent activation of MPL by mutant CALR is observed even when both the internalizations from the cell surface and transportation to the cell surface of MPL are blocked [29]. Removal of MPL and CALR from the cell surface rapidly attenuates the downstream activation [27]. This evidence suggests that the mutant CALR activates MPL on the cell surface (Fig. 2), and activation persists during endocytosis. Secreted mutant CALR activates MPL on the cell surface when cells express mutant CALR [30] (Fig. 2), while extracellular mutant CALR is unable to activate MPL expressed on the cell surface when cells do not express mutant CALR [20, 23] (Fig. 3). This is consistent to the notion that the mutant CALR recognizes the immature form of MPL, which is not expressed on the cell surface in cells that do not express mutant CALR.

Fig. 3

Cell-autonomous activation of MPL in CALR-mutant cells. Secreted mutant CALR does not exhibit a paracrine capacity to activate mature MPL on the cell surface in cells not harboring mutant CALR. However, mutant CALR activates MPL on cells expressing mutant CALR, presumably due to an interaction with and activation of immature MPL on the cell surface. It is not clear whether the activation of the mutant CALR–MPL complex transported from the intracellular compartment, or the activation of MPL by secreted mutant CALR, plays a dominant role in cellular transformation

Mutant CALR beyond the MPL-JAK2 axis

It is now clear that the mutant CALR plays a causal role in the development of MPN by interacting with and activating MPL. Besides the MPL-JAK2 axis, mutant CALR may play additional role(s) in the development of MPN. CALR del52 binds to Friend leukemia virus integration 1 (Fli1), and accumulates on the MPL promoter with an elevated level of Fli1 in Ba/F3 cells [31]. This is associated with an increase in MPL expression, suggesting that the mutant CALR promotes tumorigenesis by modulating transcription through interactions with transcription factors in the nucleus.

wt CALR is a part of the peptide loading complex (PLC), which mediates loading of peptides from intracellular proteins onto the major histocompatibility complex I (MHC-I). Ablation of wt CALR expression from HEK293T cells by gene editing results in the reduction of MHC-I on the cell surface, which was not restored by the expression of mutant CALR, implying that mutant CALR is defective in its role in the PLC [32]. Mutant CALR plays a dominant negative role in peptide loading onto MHC-I in wt CALR-expressing cells (32). Although the effect on MHC-I is not robust and CALR mutations are usually heterozygous, the dominant negative property of mutant CALR against MHC-I antigen presentation may contribute to the development of MPN by allowing tumor cells to escape from immune surveillance.


A series of studies have defined mutant CALR as a context-dependent oncogene that requires MPL and displays a novel and unexpected mechanism of action in tumor biology. The underlying molecular mechanism for MPL activation is inimitable in the sense that the mutant-specific sequence generated by a frameshift mutation promotes the multimerization of mutant CALR, causing presumptive structural changes that enable the engagement of mutant CALR and MPL, using the N-glycan binding affinity of wt CALR to convey immature MPL to the cell surface for activation. Further detailed analysis, including high resolution imaging and structural analysis, is required for a more precise understanding of this molecular mechanism for cellular transformation, and will contribute to the development of novel therapeutic strategies against MPNs.


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This work was funded in part by the MEXT-Supported Program for the Strategic Research Foundation at Private Universities; MEXT’s Promotion Plan for the Platform of Human Resource Development for Cancer Project; the JSPS KAKENHI Grant #16K09859, #17H04211, #18K08372, #19K08848; grants from the Takeda Science Foundation, the SENSHIN Medical Research Foundation and the Japan Leukemia Research Fund. The funders had no role in the preparation of the manuscript.

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Correspondence to Norio Komatsu.

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Araki, M., Komatsu, N. The role of calreticulin mutations in myeloproliferative neoplasms. Int J Hematol 111, 200–205 (2020).

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  • Myeloproliferative neoplasms
  • Calreticulin
  • Thrombopoietin receptor
  • JAK2