Calreticulin (CALR) Mutations in Myeloproliferative Neoplasms

by Kamran Mirza MBBS PhD FCAP
April 16, 2026

If your test results mention a CALR mutation — sometimes written as a calreticulin mutation — this refers to a change in a gene that is found in approximately 25–35% of patients with essential thrombocythemia and primary myelofibrosis, two types of blood cancer belonging to the group called myeloproliferative neoplasms (MPNs). CALR mutations are the second most common driver mutation in these diseases, after JAK2 V617F. They confirm the diagnosis of an MPN, help distinguish between MPN subtypes, and — in primary myelofibrosis — carry important prognostic information depending on which specific type of CALR mutation is present. This article explains what CALR mutations are, how they work, and what the result means for your care.

What the test looks for

The CALR gene encodes a protein called calreticulin. In a healthy cell, calreticulin lives inside a structure called the endoplasmic reticulum — the cell’s protein-folding factory, a network of membranes where newly made proteins are checked and shaped before they go to work. Calreticulin helps other proteins fold into the correct three-dimensional shape and acts as a quality controller, holding onto proteins that are not yet correctly formed and releasing them only when they are ready.

CALR mutations change the protein in a very specific way. They alter the last section of the calreticulin protein — called the C-terminus, the tail end of the protein chain — by deleting or inserting a short stretch of genetic code. This frameshift, as it is called, causes the cell to read the gene’s instructions in the wrong frame from that point onward, producing a completely new tail sequence that does not exist in the normal version of the protein.

This new tail is the key to understanding why the mutation causes disease. The normal calreticulin protein has a specific sequence at its tail that acts like a retention signal — a molecular tag that keeps it anchored inside the endoplasmic reticulum. The mutant tail does not carry this tag. Instead, it acquires a new property: it can bind to a receptor on the surface of blood-forming cells called the MPL receptor, also known as the thrombopoietin receptor. This receptor normally responds only to thrombopoietin — a hormone the body releases to signal that more platelets are needed. When it receives that signal, it activates a growth pathway inside the cell called JAK-STAT, which tells the cell to divide and produce more platelets.

The mutant calreticulin protein acts like a fake key that fits the MPL receptor’s lock. It binds to the receptor and activates JAK-STAT signaling continuously — even when the body is not sending any signal requesting more platelets. The cells continue producing platelets (and, in some cases, other blood cells) without the normal check on their activity. This is what drives the overproduction of blood cells seen in CALR-mutated MPNs.

This mechanism is worth noting because it reaches the same destination as JAK2 V617F — persistent, abnormal JAK-STAT activation — but by a completely different route. JAK2 V617F locks a signaling protein directly in the on position. CALR mutations create a rogue protein that jams the receptor from the outside. Both result in cells that produce too many blood cells without proper regulation.

CALR type 1 and type 2: two mutations with different implications

CALR mutations are not all the same. They fall into two main categories based on what change in the genetic code has occurred, and these two types carry different clinical implications, particularly in primary myelofibrosis.

Type 1 CALR mutation

A type 1 CALR mutation involves the deletion of 52 base pairs — a 52-letter stretch of the gene’s code — from the region that encodes the protein’s tail. This produces a mutant calreticulin with a specific new tail sequence. Type 1 mutations account for approximately 53% of all CALR mutations in MPNs.

In primary myelofibrosis, type 1 CALR mutations are associated with a more favorable prognosis than JAK2-mutated or triple-negative myelofibrosis (in which no driver mutation is found), but with a more aggressive disease course than type 2 CALR. Patients with type 1 CALR-mutated myelofibrosis tend to have higher rates of fibrotic progression over time. Despite this, type 1 CALR myelofibrosis generally responds well to JAK inhibitor therapy.

In essential thrombocythemia, type 1 CALR mutations are associated with a slightly higher risk of progression to myelofibrosis than type 2, though both types carry a lower risk than JAK2-positive ET.

Type 2 CALR mutation

A type 2 CALR mutation involves the insertion of 5 base pairs — a 5-letter addition — into the same region of the gene’s tail. This produces a different mutant tail sequence from type 1, though both activate the MPL receptor by the same general mechanism. Type 2 mutations account for approximately 32% of CALR mutations in MPNs.

Type 2 CALR myelofibrosis carries the most favorable prognosis of the main MPN driver mutation groups. Patients with type 2 CALR myelofibrosis tend to have higher platelet counts, a clinical picture that resembles ET more than classic myelofibrosis, lower rates of fibrotic progression, and longer overall survival compared to JAK2-positive or type 1 CALR myelofibrosis. In essential thrombocythemia, type 2 CALR is associated with a particularly ET-like phenotype.

Other CALR mutation types

A smaller proportion of CALR mutations — approximately 15% — are classified as other types, meaning they involve different deletions or insertions in the same region. These are grouped into type 1-like and type 2-like categories based on the properties of the mutant tail they produce, and their clinical implications broadly follow the type 1 or type 2 patterns accordingly.

Why is the test done

CALR testing is done for three reasons: to confirm the diagnosis of an MPN, to distinguish between MPN subtypes when the clinical picture is unclear, and — in primary myelofibrosis — to provide prognostic information through the type 1 versus type 2 distinction.

CALR mutations are found almost exclusively in essential thrombocythemia and primary myelofibrosis, not in polycythemia vera. This makes CALR testing diagnostically useful: if a patient has blood test abnormalities suggesting an MPN and tests positive for a CALR mutation, this both confirms the MPN diagnosis and makes polycythemia vera essentially impossible. Conversely, a patient suspected of having ET or primary myelofibrosis whose JAK2 V617F test is negative will have CALR testing performed next, since CALR is the most likely alternative driver mutation in those conditions.

CALR, JAK2, and MPL mutations are almost always mutually exclusive — a blood-forming stem cell virtually never carries more than one driver mutation at the same time. This means the three are tested as a panel: finding a CALR mutation effectively rules out JAK2 V617F and MPL mutations as co-drivers in the same clone.

Who should be tested

CALR testing is recommended for patients in whom an MPN is suspected, even if JAK2 V617F testing has been negative. This applies to:

Patients with a persistently high platelet count where essential thrombocythemia is suspected, and JAK2 V617F was not found.
Patients with bone marrow scarring, anemia, or an enlarged spleen where primary myelofibrosis is suspected, and JAK2 V617F was not found.
Patients with an unexplained blood clot in an unusual location — such as the portal vein or splenic vein — where an underlying MPN is being investigated, and JAK2 testing was negative.

In many centers, JAK2, CALR, and MPL are now tested simultaneously as part of a molecular panel, rather than sequentially. If all three are negative in a patient with clinical and bone marrow features of an MPN, the patient is classified as triple-negative, which carries its own prognostic implications — particularly in myelofibrosis, where triple-negative disease is generally associated with the most aggressive behavior.

How the test is performed

CALR testing is usually performed on a blood sample. Because CALR-mutated MPN cells circulate in the blood, a simple blood draw provides sufficient material — no bone marrow biopsy is needed for the molecular test itself. However, a biopsy may still be required for the overall MPN diagnosis.

The test detects CALR mutations by molecular testing — either fragment analysis (which identifies the size change caused by the insertion or deletion) or next-generation sequencing (NGS), which reads the genetic code of the CALR gene in detail and identifies the exact nature of the mutation. NGS can also test for JAK2, MPL, and other clinically relevant genes simultaneously in a single panel.

How results are reported

The CALR result is reported as mutation detected or not detected. When a mutation is found, the report will specify:

The mutation type — type 1 (52-bp deletion), type 2 (5-bp insertion), or another named variant. This is the most clinically important piece of information beyond the positive/negative result.
The specific mutation in genetic notation — for example, CALR c.1092_1143del for a type 1 deletion, or CALR c.1154_1155insTTGTC for a type 2 insertion.
The variant allele frequency (VAF) is the proportion of the tested cells carrying the mutation. A higher VAF indicates a greater proportion of blood-forming cells that derive from the mutated clone. In MPNs, VAF can be tracked over time to monitor whether the abnormal clone is growing or stable.

A negative result means no CALR mutation was found in the regions analyzed. If JAK2 testing was also negative, the report or your hematologist will indicate whether MPL testing is the recommended next step.

What the result means

CALR mutation detected in essential thrombocythemia

A positive CALR result in the context of essential thrombocythemia confirms that the MPN is being driven by the calreticulin mutation rather than JAK2 V617F. This has clinical behavior that differs from JAK2-positive ET and is worth understanding.

CALR-mutated ET is generally associated with a higher platelet count at diagnosis than JAK2-positive ET, and — counterintuitively — with a somewhat lower risk of blood clots. This is thought to reflect the fact that JAK2-positive ET causes overproduction of red cells and white cells in addition to platelets, which contributes more to blood thickening and clot risk, while CALR-mutated ET is more purely platelet-driven. The lower risk of clots in CALR-positive ET compared with JAK2-positive ET is accounted for in risk stratification. However, age and other clinical factors remain the primary determinants of how aggressively clot risk is managed.

The risk of progression to myelofibrosis is lower in CALR-mutated ET than in JAK2-positive ET overall, and lower in type 2 than in type 1 mutations. The risk of transformation to acute myeloid leukemia is very low in both groups.

Treatment for CALR-mutated ET follows the same principles as for JAK2-positive ET: managing clot risk through low-dose aspirin, controlling platelet counts with cytoreductive drugs — medications that slow down the overproduction of blood cells — when indicated, and monitoring for signs of progression. There is no CALR-specific targeted drug currently in clinical use.

CALR mutation detected in primary myelofibrosis

In primary myelofibrosis, the CALR mutation type carries significant prognostic weight and will directly influence your hematologist’s assessment of disease risk and treatment intensity.

The driver mutation hierarchy in myelofibrosis, from best to worst prognosis, broadly runs: CALR type 2 → CALR type 1 → JAK2 V617F → MPL → triple-negative. Patients with CALR type 2-mutated myelofibrosis have the longest median overall survival, while those with triple-negative myelofibrosis have the shortest. CALR type 1 and JAK2-positive myelofibrosis fall between these extremes, with broadly similar intermediate outcomes in many studies, though CALR type 1 patients tend to do somewhat better.

These differences influence when stem cell transplantation — the only treatment currently capable of producing long-term remission in myelofibrosis — is recommended. Risk scoring systems used in myelofibrosis incorporate driver mutation type alongside clinical features such as age, blood counts, symptoms, and bone marrow scarring. Patients classified as higher-risk are more likely to be offered early transplant evaluation. Your hematologist will use the full set of results — not just CALR type — to determine your overall risk and the treatment plan.

For patients with significant symptoms — a large spleen, fatigue, night sweats, or weight loss — JAK inhibitor therapy is the main treatment option. JAK inhibitors work by blocking the same JAK-STAT signaling pathway that CALR mutations activate. They are effective in CALR-mutated myelofibrosis regardless of mutation type, and work through the same mechanism whether the driver mutation is CALR, JAK2, or MPL. For a detailed explanation of the available JAK inhibitors — ruxolitinib, fedratinib, pacritinib, and momelotinib — and how the choice between them is made, see the related article on JAK2 mutations in myeloproliferative neoplasms, which covers their indications and mechanisms.

CALR not detected

A negative CALR result means no type 1, type 2, or other detectable CALR mutation was found in the cells tested. If JAK2 V617F is also negative, the next step is usually to test for an MPL mutation. If all three are negative and clinical and bone marrow findings still support an MPN diagnosis, the patient is classified as triple-negative. Triple-negative myelofibrosis in particular carries a less favorable prognosis than CALR-positive or JAK2-positive disease, and your hematologist will factor this into the overall risk assessment.

CALR mutations and blood clots

Like JAK2 V617F, CALR mutations are associated with an increased risk of blood clots compared to the general population — though the risk is somewhat lower in CALR-positive ET than in JAK2-positive ET. The mechanism is different from JAK2-related thrombosis: CALR-driven overproduction of platelets is the primary contributor, rather than the broader blood-cell thickening seen with JAK2 mutations.

Managing clot risk remains a central part of care for CALR-mutated ET and myelofibrosis. Low-dose aspirin, cytoreductive therapy to control platelet counts, and anticoagulation are all part of the standard management toolkit for patients who have already had a clot. Your hematologist will assess your individual risk and recommend the appropriate approach.

CALR mutations are not inherited

CALR mutations found in MPNs are almost always somatic — they develop in a blood-forming stem cell during a person’s lifetime and are not present in any other cell in the body. They are not inherited and cannot be passed to children. A positive CALR result does not affect your biological relatives’ risk of MPN.

This is distinct from rare germline CALR variants, which have been described in a small number of families with inherited MPN predisposition. These are uncommon and are typically suspected only in someone with a strong family history of MPN. If there is any concern about hereditary risk in your family, your hematologist can arrange further assessment.

What happens next

For patients with newly diagnosed CALR-mutated ET, management focuses on assessing clot risk and deciding whether cytoreductive treatment is needed to lower the platelet count. Most patients with ET — regardless of mutation type — are initially managed with watchful waiting and low-dose aspirin, with cytoreductive drugs added for higher-risk patients. Your hematologist will explain your risk category and what monitoring will entail.

For patients with newly diagnosed CALR-mutated primary myelofibrosis, the CALR mutation type — together with your clinical features and overall risk score — will be used to determine how aggressively the disease needs to be managed. If symptoms are present, JAK inhibitor therapy will be discussed. If you are younger or have a higher-risk disease, early evaluation for stem cell transplantation may be recommended. Your hematologist will walk through the full treatment plan based on your individual situation.

For patients in whom CALR testing has returned negative, and JAK2 testing is negative, MPL mutation testing will be the next step. If all three tests are negative and an MPN is still suspected based on clinical and bone marrow findings, your hematologist will discuss what triple-negative status means for your specific diagnosis and management.

Questions to ask your doctor

Do I have a CALR mutation — and if so, is it type 1, type 2, or another variant?
How does my CALR type affect my prognosis compared to what it would be with a JAK2 mutation or a different CALR type?
If my CALR result is negative, will MPL testing be done — and what would a triple-negative result mean?
How does my CALR result factor into my overall risk score, and what risk category am I in?
Do I need treatment now, or is watchful waiting appropriate for my situation?
If I have myelofibrosis, is stem cell transplantation being considered, and what would the timing be?
Will my CALR variant allele frequency be monitored over time, and what would a rising level mean?