Celebrating the discovery of mutated CALR

CALR white paper

Learn more. Download our MPNRF white paper about the mutated CALR discovery and the evolution of individualized MPN medicine.

In related news:
MPNRF is featured in a February 2024 Precision Oncology article about the CALR discovery: “Years After Genetic Finding, Drugs Targeting CALR-Mutant Myeloproliferative Neoplasms Enter Trials.”
Read the full article >


CALR mutation 10 years after discovery:
The Evolution of Personalized Medicine Changes Research and Treatment Implications

Drug discovery relies on resources and collaboration beyond the boundaries of the laboratory. When MPN Research Foundation was founded in 1999,meaningful research on the blood cancers now collectively known as myeloproliferative neoplasms (MPNs) was scarce, including essential thrombocythemia (ET), polycythemia vera (PV),  and myelofibrosis (MF).

Established with a mission to stimulate original MPN research in pursuit of new treatments — and eventually a cure — MPNRF has since played a key role funding some of the most important work over the last two decades, including the foundational research that led to discovery of a mutation in the calreticulin gene (CALR).

One of the MPN Research Foundation’s first grants (2000) funded initial laboratory work specifically exploring genetic drivers of blood cancers, including MPNs. This unlocked subsequent research in the field that led to the discovery of the JAK and MPL mutations. But these important findings still left questions for patients with neither the JAK nor MPL mutation. So in 2009 and 2011, Robert Kralovics, PhD, was awarded two grants from MPNRF to pursue other mutations that might be at play, which directly led to his discovery of the CALR mutation just a few years later.

These awards are representative of the spirit of MPN Research Foundation, with early funding contributing to a long-term, practice-changing moment in hematologic cancers, critical to the identification of the role of CALR mutations.

In 2013, two seminal papers were published back-to-back in the same issue of the New England Journal of Medicine, describing mutations that had been identified in CALR in a subgroup of patients with ET or MF. These mutations appeared to be mutually exclusive of the Janus kinase 2 (JAK2) and thrombopoietin receptor (MPL) mutations, which are found in the majority of ET and MF patients. The CALR gene encodes a protein called calreticulin, which is believed to play a role in protein folding, calcium regulation, gene activity, cell proliferation, migration, adhesion, and apoptosis.

Using different strategies, the two teams of researchers demonstrated that in its mutated state, CALR is a major driver of MPN in patients without JAK2 and MPL mutations. And together, each investigation validated the other.

In one paper, a team led by Dr. Kralovics performed exome sequencing on samples from 6 patients and identified acquired insertion or deletion CALR mutations in all of them. Targeted sequencing was then conducted on a large cohort of patients with both MPNs and other myeloid cancers.

At the same time, a team led by Jyoti Nangalia, MBBS, PhD, now a member of MPNRF’s Scientific Advisory Council, came at the driver mutations question from a different angle. She performed exome sequencing on samples obtained from a large cohort of 151 patients with MPNs. This provided an unprecedented view of the mutational landscape in MPNs, allowing for CALR mutations to be identified in patients with ET or primary MF without JAK2 or MPL mutations.

The CALR aha! moment

“There were so many memorable moments – from that special day of discovery, to calling one of our patients in July 2013 to kindly donate another blood sample so we could confirm the mutation,” Dr. Nangalia recalls. “I remember thinking she was likely the first person in the world with a confirmed CALR mutation and a cause for her disease.”

The team went on to implementing the test in clinic within a few months, and testing all of their historical patient samples to confirm their diagnosis.

This work helped to fill a large gap in the knowledge of the genetic origins of MPNs, by identifying the most common mutation in patients without JAK2 or MPL mutations. The discovery reads like a momentous moment in time, but it was actually the culmination of years of investigating the genetic complexity of these disorders.

CALR mutation and its relationship to MPNs has had a major impact, according to Ann Mullally, MD, a physician-scientist at Brigham and Women’s Hospital/ Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, who is also a member of MPNRF’s Scientific Advisory Council.

Mutations offer clues toward diagnosis and prognosis

That paradigm changed with the identification of the CALR mutation, which is the second most common mutation after JAK2. “Its presence is very definitive for making a diagnosis, since the mutation is not found in other diseases,” Dr Mullally explains. “So, I think that [discovery] was very, very, very important.”

Knowing the type of mutation also helps in determining prognosis. “We know that there are differences as to whether you have MPN with this mutation versus MPN with the JAK2 mutation, for all different types of complications and prognosis,” Dr. Mullally adds. “In and of itself, just being able to identify whether somebody has the mutation can already be very helpful in terms of counseling patients about what you know their risks are.”

Perhaps most exciting, ongoing research has yielded promising future implications for patients, as CALR represents a new therapeutic target and raises the possibility of new treatment approaches that are more personalized to the patient, compared to the current one-size-fits-all approach to MPNs, whatever the identified driver mutation(s). Rare disease research, however, takes time.

Moving into clinical trials directly targeting CALR

Dr Mullally notes that a clinical trial of a mutant specific CALR antibody designed to target this mutation was presented at the 2022 American Society of Hematology meeting. And the first US-based clinical began in 2023.

“The 10-year anniversary of the discovery of the CALR mutation is really a time for everybody to kind of take stock,” believes Dr. Mullally. “The MPN Research Foundation has been really instrumental in this and the amount of research that’s been going on all around the world is really impressive, to understand how this mutation causes disease.”

She adds that much of the work is highly collaborative. “This involves not only what happens in the laboratory but what happens in the clinic, clinical research, and patient observations.”

For example, a research team led by Marina Kremyanskaya, MD, PhD, Icahn School of Medicine at Mount Sinai, first developed a vaccine that targets mutated CALR with the goal of enhancing the immune response in MPN patients. In a project funded by an MPNRF 2022 Thrive Initiative award, Harnessing the Immune System to Target Calreticulin Mutant Myeloproliferative Neoplasms, she and her colleagues began initial testing of the vaccine in a clinical trial in MPN patients.

Today, two companies are investigating CALR-targeted treatments in current clinical trials, with potential to be available to patients if approved in the coming years.

MPNRF has awarded more than $18 million for blood cancer research since it was founded, including supporting researchers doing preclinical testing and funding very early full genome sequencing projects at a time when the human genome project first suggested this might be feasible. Today, some of the investigators who received the Foundation’s earliest awards are now leaders in the field.
Read our white paper with additional personal insights on the CALR discovery and the evolution of individualized medicine.