Primary myelofibrosis

Primary myelofibrosis is a condition characterized by the buildup of scar tissue (fibrosis) in the bone marrow, the tissue that produces blood cells. Because of the fibrosis, the bone marrow is unable to make enough normal blood cells. The shortage of blood cells causes many of the signs and symptoms of primary myelofibrosis.

Initially, most people with primary myelofibrosis have no signs or symptoms. Eventually, fibrosis can lead to a reduction in the number of red blood cells, white blood cells, and platelets. A shortage of red blood cells (anemia) often causes extreme tiredness (fatigue) or shortness of breath. A loss of white blood cells can lead to an increased number of infections, and a reduction of platelets can cause easy bleeding or bruising.

Because blood cell formation (hematopoiesis) in the bone marrow is disrupted, other organs such as the spleen or liver may begin to produce blood cells. This process, called extramedullary hematopoiesis, often leads to an enlarged spleen (splenomegaly) or an enlarged liver (hepatomegaly). People with splenomegaly may feel pain or fullness in the abdomen, especially below the ribs on the left side. Other common signs and symptoms of primary myelofibrosis include fever, night sweats, and bone pain.

Primary myelofibrosis is most commonly diagnosed in people aged 50 to 80 but can occur at any age.

Primary myelofibrosis is a rare condition that affects approximately 1 in 500,000 people worldwide.

Mutations in the JAK2, MPL, and TET2 genes are associated with most cases of primary myelofibrosis. The TET2 gene provides instructions for making a protein whose function is unknown. The JAK2 and MPL genes provide instructions for making proteins that promote the growth and division (proliferation) of blood cells.

The proteins produced from the JAK2 and MPL genes are both part of a signaling pathway called the JAK/STAT pathway, which transmits chemical signals from outside the cell to the cell's nucleus. The protein produced from the MPL gene, called thrombopoietin receptor, turns on (activates) the pathway, and the JAK2 protein transmits signals after activation. Through the JAK/STAT pathway, these two proteins promote the proliferation of blood cells, particularly a type of blood cell known as megakaryocytes.

Mutations in either the JAK2 gene or the MPL gene that are associated with primary myelofibrosis lead to overactivation of the JAK/STAT pathway. The abnormal activation of JAK/STAT signaling leads to overproduction of abnormal megakaryocytes, and these megakaryocytes stimulate another type of cell to release collagen. Collagen is a protein that normally provides structural support for the cells in the bone marrow. However, in primary myelofibrosis, the excess collagen forms scar tissue in the bone marrow.

Although mutations in the TET2 gene have been found in approximately 17 percent of people with primary myelofibrosis, it is unclear what role these mutations play in the development of the condition.

Many people with primary myelofibrosis do not have a mutation in any of the known genes associated with this condition. Researchers are working to identify other genes that may be involved in the condition.

Read more about the JAK2, MPL, and TET2 genes.

See a list of genes associated with primary myelofibrosis.

This condition is generally not inherited but arises from gene mutations that occur after conception. This alteration is called a somatic mutation.