Genetic Mutations Associated with Myeloproliferative Neoplasms (MPNs)

Myeloproliferative neoplasms (MPNs) are blood disorders caused by an excessive production of blood cells in the body. There are a number of gene mutations, such as JAK2, MPL, CALR, BCR-ABL, and ASXL1, that affect blood cell formation and can cause MPNs. These mutations occur in cells that have the ability to survive in the body long term.

Most of the time, MPNs are developed by chance and are very rarely due to an inherited gene. This means they are acquired in the body and are not passed on from parent to child. Recent estimates suggest that MPN-causing mutations may occur decades before a diagnosis is made.

How genes and gene mutations form and lead to MPNs is an ongoing area of research at the Weill Cornell Medicine Silver Myeloproliferative Neoplasms (MPN) Center and around the world.

These are some of the most common genetic mutations associated with MPNs:


The JAK2 gene is part of a network in the body that allows cells to communicate with their environment. JAK2 encodes a protein in the family of Janus-associated kinases (JAKs) that is part of the signaling system that tells blood forming cells in the bone marrow to divide and mature into functional blood cells.

JAK2 acts as a relay between growth factors (aka cytokines) outside the cell interacting with cell receptors on the cell surface and the internal cell machinery. If you think of the cytokines as your cell phone signal, the receptors are like the antenna in your cell phone and JAK2 helps the phone figure out what to do with the cell phone signal. JAK2 makes the signal stronger even when it doesn’t need to be and when it’s not good to do so. In this way, JAK2 is positioned to enhance the bodily signals to promote unnecessary blood cell production.

The JAK2 gene mutation is the most common mutation found in myeloproliferative neoplasms (MPN) and occurs in nearly all people who have polycythemia vera (PV) and ~50% of people who have essential thrombocythemia (ET) or myelofibrosis (MF). Mutations in JAK2 over-activate the normal controls governing blood cell production and cause the body to make the wrong number of and type of blood cells. The mutated JAK2 sends signals even when it isn’t supposed to do so, and can lead to excess blood cell production.

JAK2 gene mutations are not hereditary and are acquired at random. Because of this, the gene mutation is not passed on from parent to child.


The calreticulin gene, also known as CALR, creates a protein in the body called calreticulin. The calreticulin protein helps ensure new proteins are doing their job, managing calcium levels in cells, and other cell functions. Mutations of the CALR gene cause disturb the normal functions of CALR and make mutant CALR drive the overproduction of blood cells, leading to myeloproliferative neoplasms (MPNs).

Like JAK2 mutations (see above) mutant CALR enhances cytokine signaling leading to abnormal regulation of blood cell production. Mutant CALR appears to primarily act by boosting signals from a particular cytokine system (thrombopoietin, THPO, and its receptor MPL) that normally regulates platelet production and blood stem cell activity.

The CALR mutation is acquired after birth and is generally not inherited by one’s parents and not passed to your children.

CALR mutations are the second most common genetic abnormality (after JAK2) associated with essential thrombocythemia (ET) and primary myelofibrosis (MF).


The myeloproliferative leukemia, or MPL gene, creates a protein that helps control the number of blood cells the body makes in the bone marrow, particularly platelets. Mutations of the MPL gene overstimulate blood cell production causing the body to either make abnormal blood cells or too many platelets.

Mutations in this gene can be present in patients with myeloproliferative neoplasms such as essential thrombocythemia and primary myelofibrosis.


BCR and ABL are two gene types that have the ability to form together, known as a fusion gene. This is called a BCR-ABL mutation and happens when pieces of both genes break off and switch places. This mutation has the ability to affect the bone marrow and white blood cells.

This gene mutation can be present in patients with chronic myeloid leukemia (CML) and other types of leukemias.


The ASXL1 gene is responsible for making proteins involved in a process in the body known as chromatin remodeling. Chromatin helps package DNA into chromosomes and through chromatin remodeling, the ASXL1 protein controls the expression of many genes.

The precise mechanisms by which mutations of the ASXL1 gene lead to blood cancers is not fully known. But mutant ASXL1 disrupts normal regulation of gene activity in blood forming cells and allows these cells to grow and divide abnormally. These mutations are associated with a number of cancers of the blood-forming cells, including MPNs, chronic myelomonocytic leukemia (CMML), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

ASXL1 mutations are acquired during a person’s lifetime and are only present in the cancerous cells.

Richard T. Silver MD Myeloproliferative Neoplasms Center 525 East 70th St., Starr Pavillion, 3rd Floor New York, NY 10021