What Is a CALR Mutation? Causes, Testing, and Prognosis

A CALR mutation is a change in a gene inside some blood-forming cells. You acquire it during life rather than inheriting it, and it pushes the bone marrow to make too many platelets. It is one of the main known triggers of a group of slow-growing blood cancers, most often essential thrombocythemia and myelofibrosis. Compared with the more common JAK2 mutation, CALR usually comes with a gentler course, though not a risk-free one. The exact type of CALR change, listed on many test reports, matters nearly as much as finding it at all.

What the CALR Gene Normally Does and What Goes Wrong

The CALR gene makes calreticulin, a protein that lives inside the cell compartment where new proteins are built and packaged.¹ It holds more than half of the calcium stored there and releases it quickly when the cell needs it.² It also works as a quality checker, helping newly made proteins fold into the right shape.³

In people with these blood cancers, the mutation deletes or inserts a few letters near the end of the gene, scrambling the protein’s tail.⁴ The change shifts the reading frame, so the end of the protein is built from the wrong amino acids. The normal tail is negatively charged and binds calcium. The new tail is rich in positively charged building blocks, which changes how the protein behaves.

The new tail lets mutant calreticulin proteins stick together in clusters, which normal ones do not.⁵ The clusters latch onto the receptor for thrombopoietin, the hormone that tells the marrow to make platelets.⁶ The receptor then stays switched on without any hormone, so platelet-making cells keep multiplying.⁷

With the receptor locked on, the cells ignore the body’s normal control of the platelet hormone, which is why CALR disease tends to push platelets higher than other mutations do. This runaway growth signal causes myeloproliferative neoplasms (MPNs), a group of chronic blood cancers in which the marrow overproduces blood cells.

The two conditions CALR causes most often are essential thrombocythemia (ET) and myelofibrosis (MF). ET mainly means a high platelet count, often found by chance on a routine blood test. Myelofibrosis means the marrow gradually fills with scar tissue and struggles to make normal blood. CALR is the second most common driver of both, after JAK2. Calling these cancers is accurate, but for many people with ET the condition behaves as a long-term illness managed over decades.

The change is found in blood-forming stem cells and their descendants, not in skin, muscle or other tissues. Because only some marrow cells carry it, a person can have a mix of mutated and normal blood cells.

What Causes a CALR Mutation and Can It Be Inherited

The disease-causing CALR mutation appears in one blood-forming stem cell during adulthood and is not present in the rest of the body. It is copied only into that cell’s descendants, never into eggs or sperm, so it cannot be passed to your children. It is rare in children with ET, which fits a change that builds up with age.⁸

Once one stem cell has the change and gains a growth edge, its descendants slowly take up a larger share of the marrow. That is why disease usually shows up in midlife or later. One caveat: some unusual CALR variants found at about half of blood cells may be inherited ones rather than the disease-causing kind.⁹

No lifestyle habit, diet or exposure has been shown to cause the mutation. Random copying errors as stem cells divide over a lifetime are the accepted explanation. Rare familial clusters of MPNs do exist, so mention any relatives with blood disorders to your doctor.

Because the mutation is acquired, routine testing of relatives is not usually advised. A doctor may consider it only if relatives have unexplained high blood counts.

How CALR Mutations Are Found and What Your Report Means

Testing uses DNA from a blood sample, sometimes bone marrow.¹⁰ The lab extracts DNA from your blood cells and looks at the CALR gene, usually the part near the end where disease mutations cluster. Results often take days to a couple of weeks, depending on the lab, and may arrive as a written report with technical notation.

Labs use several methods. Most catch the usual mutations, and the most sensitive detect it in as few as 1 in 100 blood cells.¹¹ Simpler screening tests can miss rare mutation forms or very low levels, so a lab may confirm with sequencing.¹² Labs vary in sensitivity. JAK2 is the most common driver, so many labs test it first and add CALR if it is negative. A normal JAK2 result therefore does not rule out an MPN.

Reports often give a code starting with “c.”, which describes the exact change in the gene’s DNA. If the wording is unfamiliar, the key items to look for are the type (1, 2 or other) and the share of cells carrying it.

Type 1, a 52-letter deletion, and type 2, a 5-letter insertion, make up over 80% of CALR mutations.¹³ Reports may say “type 1-like” or “type 2-like”; about 65% of mutations fall in the type 1-like group and 32% in type 2-like.¹⁴ Some rare variants are labelled “of uncertain significance,” meaning experts cannot yet say whether they drive disease.¹⁵

Your report may also list the allele burden, or VAF. This is the share of your blood cells carrying the mutation, often written as a percentage. CALR disease usually shows a higher share than JAK2 disease. Doctors may also follow this share during treatment.

People with none of the three main mutations (JAK2, CALR, MPL) are called triple-negative.¹⁶ In myelofibrosis, triple-negative disease has a poorer outlook; it made up about 6% of patients in one large group.¹⁷ Triple-negative ET, though, tends to do better than JAK2 ET.¹⁸

How CALR Disease Differs From JAK2 Disease

In ET, people with CALR are usually younger and more often male than those with JAK2.¹⁹ Their platelets run higher, around 990 versus 860 billion per litre on average, with lower hemoglobin and white cells.²⁰

CALR ET does not turn into polycythemia vera, while JAK2 ET can.²¹ Polycythemia vera means too many red blood cells, and it is driven mainly by JAK2.

People with CALR report fewer MPN symptoms than those with JAK2 or MPL.²² Fatigue, weight loss and night sweats are notably milder on average.²³ Those are group averages, though. Some people with CALR have heavy symptoms, and some with JAK2 have almost none. Despite higher platelets, clot risk is lower in CALR disease, and doctors weigh age and clot history more than the count alone.

Myelofibrosis is somewhat different. There too, CALR patients are younger, and they are less often anemic or transfusion dependent. Some still have low counts, so experience varies.

Blood Clot Risk With a CALR Mutation

In ET, about 5% of people with CALR have a clot within 10 years, compared with 14.5% with JAK2.²⁴ In myelofibrosis, CALR also roughly halves clot risk compared with JAK2.²⁵ Lower risk is not zero risk.

Age over 60 and any past clot remain the biggest factors. Smoking, high blood pressure and diabetes add risk and are worth controlling. Clots in MPNs can occur in arteries, causing heart attack or stroke, or in veins, such as a leg vein, and sometimes in unusual places like abdominal veins. Sudden severe headache, one-sided weakness, trouble speaking, chest pain, sudden vision change, or a painful swollen leg need urgent medical attention rather than waiting for the next appointment.

Low-dose aspirin is common in ET but not right for everyone. Very high platelets can cause bleeding, which affects the aspirin decision, so ask your doctor whether aspirin suits your situation.

Prognosis and Life Expectancy

In myelofibrosis, median survival was about 17.7 years with CALR versus about 9 years with JAK2.²⁶ That advantage comes from type 1: median survival was about 26 years with type 1 versus about 7 years with type 2, similar to JAK2.²⁷ CALR’s benefit holds after accounting for other risk markers.²⁸ So knowing your type gives a more accurate picture than knowing only that you have CALR, and the CALR label alone can be falsely reassuring for type 2 disease.

A median is the point where half of people live longer, and it cannot say how long one person will live. These numbers come from groups diagnosed years ago, before newer treatments, and they include people diagnosed late or at older ages, which pulls the figures down. Your age at diagnosis matters greatly, and CALR patients are often younger.

In ET, overall 20-year survival was similar across mutations, around 86% with CALR.²⁹ The main difference is not how long people live but what complications they face. Only 48% of CALR ET patients stayed free of myelofibrosis at 20 years, compared with 87% for JAK2.³⁰ The risk concentrates in type 1: about 26% developed myelofibrosis by 15 years, versus about 5-7% for type 2 or JAK2.³¹ That is a reason for long-term follow-up rather than a prediction that scarring will happen. Turning into leukemia is not more likely with CALR than with JAK2.³² Signs of progression include growing tiredness, falling hemoglobin, or an enlarging spleen that causes belly fullness. Night sweats or weight loss count too. Regular blood tests catch changes early. Your doctor may repeat marrow testing if counts shift.

Treatment Options for CALR-Mutated Disease

Low-risk ET is often managed with aspirin and monitoring, while higher-risk patients get count-lowering drugs like hydroxyurea. Treatment depends on your clot risk category, age, symptoms and other health conditions, not on the CALR result alone. Hydroxyurea lowers platelet counts by slowing the marrow, which reduces clot risk in higher-risk patients, but aspirin and hydroxyurea leave the share of mutated cells unchanged.³³

Interferon works on the immune system and can reduce the mutated cell population itself. It lowered the mutation share in about 65% of CALR ET patients, sometimes to undetectable.³⁴ A falling share suggests it is acting on the underlying disease, though doctors are still studying what that means for long-term outcomes, and lowering it may not yet be proven to prevent scarring. Interferon is given as injections, often weekly or less. Flu-like tiredness and mood changes can occur. It is often favored in younger people and in pregnancy. Ruxolitinib treats myelofibrosis symptoms and spleen size, and CALR patients often start it younger.³⁵

Because the mutant tail sits only on diseased cells, it is a target new drugs can aim at.³⁶ Antibodies that steer immune T cells to mutant cells are in early trials, including JNJ-88549968 and INCA035784.³⁷ They killed both type 1 and type 2 mutant cells in lab tests.³⁸

Early trials test safety first, so benefit is uncertain. To explore one, ask your specialist or search trial registries using the trial numbers. Specialist MPN centers are most likely to offer them.

Living With a CALR Mutation Day to Day

Useful questions for your hematologist: Which CALR type do I have, and how does it change my outlook? What is my clot risk category, and do I need aspirin or other drugs? How often will I be tested? Is interferon or a trial right for me?

Stay active and hydrated, especially on long flights. Tell surgeons and dentists about your condition. Keep track of symptoms like fatigue so you can report them at visits.

Pregnancy is possible but needs specialist care. Some drugs are unsafe in pregnancy, so plan ahead.