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What Causes Myeloproliferative Neoplasms (MPNs)?

Updated on April 13, 2021
Medically reviewed by
Todd Gersten, M.D.
Article written by
Heather Lapidus Glassner

Myeloproliferative neoplasms (MPNs) are blood cancers that involve overproduction of blood cells in the bone marrow. There are three classic types of MPNs. In primary myelofibrosis (MF or PMF), abnormal blood cells grow too quickly, and scar tissue forms in the bone marrow. In essential thrombocythemia (ET), platelets are overproduced. In polycythemia vera (PV), too many red blood cells are produced. Some types of leukemia, including chronic myeloid leukemia (CML), are also considered types of MPN. MPNs are considered rare because fewer than six people in 100,000 are diagnosed each year in the United States.

Like other cancers, myeloproliferative neoplasms (MPNs) are caused by genetic mutations that allow cells to divide and grow in a disorganized way. There are two main types of mutations, inherited and acquired.

Acquired mutations:

  • Happen over the course of a person’s life
  • Are caused by normal aging and exposure to carcinogens, such as radiation, certain chemicals, smoking, and some viruses
  • Are present in the DNA of some cells

Inherited mutations:

  • Are passed down from parents to children
  • Are present in the DNA of all cells at birth
  • Occur far less commonly

Most cancer is caused by acquired mutations. The cause of the mutation is usually unknown. In a few cases, MPNs are related to inherited mutations, but MPNs are generally not considered to be inherited diseases. It is still unclear why some people develop MPNs and others do not.

Watch as MPN expert Dr. Ruben Mesa explains the causes of myeloproliferative neoplasms.

How Cells Transform Into Cancer

Normal cells divide in a regular, ordered fashion, forming new cells that are exact copies to replace old ones. Certain genes in each cell are responsible for telling cells when to divide and when to stop dividing. Other genes identify and fix problems in DNA that are copied incorrectly, or cause cells with bad DNA to self-destruct rather than keep multiplying. If a genetic mutation causes one or more of these genes to turn off in some cells, the cells can divide at a faster rate without regulation or order, becoming more and more mutated. Mutations may accumulate, further speeding the unchecked growth of abnormal cells. When these disordered cells begin to invade nearby tissues or break off and migrate to other locations, they have become cancerous.

Risk Factors for MPNs

It is important to note that while science is good at finding correlations — or apparent relationships — between factors and disease, correlation does not prove the factor causes the disease. Many risk factors for MPNs have been identified and are being studied for their role in the development of the disease.

Since genetic mutations cause MPNs, risk factors for MPNs include anything that can encourage mutations.

Age

Mutations in DNA are inevitable, and they accumulate with age. Researchers theorize that in rapidly dividing tissues, such as blood stem cells, tens of thousands of mutations likely accumulate by age 60. However, cancer only develops in a small percentage of people.

The three classic types of MPNs are generally diagnosed in people over 50 years of age. Polycythemia vera (PV) and essential thrombocythemia (ET) tend to be diagnosed around 60 years of age. While increased age is a risk factor in ET, 20 percent of cases develop in people under age 40. Primary myelofibrosis (MF) is most commonly diagnosed in people older than 50.

Risk for chronic myeloid leukemia (CML) goes up with age. Chronic neutrophilic leukemia (CNL) does not have any known risk factors. The median age for CNL diagnosis is 66 years, but people from ages 15 to 86 have been diagnosed with CNL.

Inherited Factors

While MPNs are not considered to be inherited diseases, it is possible for more than one person in a family to have an MPN. In rare cases, MF and PV have been found to run in families.

According to the Leukemia and Lymphoma Society, PV is more prevalent among Jews of Eastern European descent than in people with other backgrounds.

Gender is a minor risk factor in some MPNs. Women are 1.5 times more likely to develop ET than men. CML is slightly more common in men than in women.

Environmental Factors

Anything that raises the risk for acquired genetic mutations also raises the risk for developing MPNs and other types of cancer. Several carcinogens have been identified as contributing to the risk for MPN.

Radiation

Exposure to radiation increases the risk for developing certain types of MPNs. Everyone is exposed to low levels of radiation from natural sources, such as the sky and the Earth. Many building materials naturally contain low levels of radiation. Some people are exposed to naturally occurring radon gas in their homes. Man-made sources of radiation include X-rays, computerized tomography (CT) or positron emission tomography (PET) scans, and radiation therapy. Although the levels of radiation most people are exposed to are low, the effects of radiation can accumulate over time and gradually cause mutations that lead to the development of MPNs in some people. People in jobs that expose them to higher levels of radiation — such as workers in nuclear power plants — may have a higher risk for developing chronic myeloid leukemia or primary myelofibrosis.

Chemicals

People who work with carcinogenic chemicals, such as benzene and toluene, may be more likely to develop primary myelofibrosis.

Smoking

Studies indicate that smoking a pack of cigarettes per day for 20 or more years may be a risk factor for polycythemia vera in women specifically.

Obesity

Women with a body mass index greater than 30 have an increased risk for developing essential thrombocythemia.

Acquired Mutations Associated With MPNs

Scientists have identified several acquired genetic mutations in blood stem cells that often play a role in the development of MPNs. The genetic mutations usually present in the three most common MPNs include the JAK2, CALR, and MPL gene markers. Mutations that disrupt the function of these genes can contribute to the uncontrolled growth of blood stem cells. Knowing which mutations are present in cancer cells helps doctors recommend effective treatment options.

According to the National Cancer Institute’s Dictionary of Cancer Terms:

  • JAK2 is a gene that makes a protein called Janus kinase 2, which sends signals in cells that promote cell growth.
  • CALR is a gene that makes a protein called calreticulin, which helps control the amount of calcium stored in cells.
  • MPL is a gene that makes a protein called the thrombopoietin receptor, which helps control the number of blood cells made in the bone marrow.
  • C-kit, also called CD117 or stem cell factor receptor, is a protein that binds to a substance called stem cell factor (SCF), which causes certain types of blood cells to grow and can lead to cancer.
  • Colony stimulating factor 3 receptor (CSF3R) is a gene that controls the growth and function of certain white blood cells.

Polycythemia Vera

In roughly 95 percent of PV cases, cancer cells have a JAK2 gene mutation. Specifically, the JAK2V617F gene is present in blood-forming cells.

Essential Thrombocythemia

In cases of ET, there may be mutations of JAK2, CALR, or MPL genes. Roughly 60 percent of ET cases involve a JAK2 gene mutation and roughly 33 percent involve a MPL mutation.

Primary Myelofibrosis

Between 50 percent and 60 percent of MF cases test positive for a JAK2 gene mutation. Estimates of cases of MF with the acquired genetic mutation CALR range from 3 percent to 24 percent. In addition, estimates range from 5 percent to 33 percent for the mutation of the MPL gene.

Chronic Myeloid Leukemia (also called Chronic Myelogenous Leukemia)

In most cases of CML, cancer cells have a genetic abnormality called the Philadelphia chromosome (Ph+). Named for the city in which doctors discovered it, this genetic abnormality affects chromosome 22, which has swapped sections with part of chromosome 9. This translocated gene is known as BCR-ABL. Atypical cases of CML may involve a mutation to the CSF3R gene.

Chronic Neutrophilic Leukemia

Mutations in the CSF3R gene are common in people with CNL.

Chronic Eosinophilic Leukemia

CEL has not been associated with a specific chromosome or genetic abnormality, but on rare occasions may be linked to an acquired mutation.

Mastocytosis

In more than 90 percent of adults and more than 40 percent of children with mastocytosis, cancer cells have an acquired genetic mutation in a protein called c-kit.

MPN Condition Guide

References
  1. An Overview of MPNs — MPN Research Foundation
  2. Diagnosis, Risk Stratification, and Response Evaluation in Classical Myeloproliferative Neoplasms — Blood
  3. Germline and Somatic Mutations: What Is the Difference? — Oncology Nursing Foundation
  4. Myeloproliferative Neoplasms (MPN) — Leukaemia Foundation
  5. Myeloproliferative Neoplasms — Leukemia & Lymphoma Society
  6. How Do Genes Control the Growth and Division of Cells? — Genetics Home Reference
  7. Aging and the Rise of Somatic Cancer-Associated Mutations in Normal Tissues — PLOS Genetics
  8. Polycythemia Vera — Genetic and Rare Diseases Information Center
  9. Essential Thrombocythemia — Genetic and Rare Diseases Information Center
  10. Essential Thrombocythemia — MPN Research Foundation
  11. Myelofibrosis — Mayo Clinic
  12. Risk Factors for Chronic Myeloid Leukemia — American Cancer Society
  13. Chronic Neutrophilic Leukemia Facts — Leukemia & Lymphoma Society
  14. Polycythemia Vera Facts — Leukemia & Lymphoma Society
  15. Chronic Myeloid Leukemia (CML) Risks and Prevention — Penn Medicine
  16. What Causes MF? — MPN Research Foundation
  17. Modifiable Lifestyle and Medical Risk Factors Associated With Myeloproliferative Neoplasms — HemaSphere
  18. Mutations — MPN Research Foundation
  19. Dictionary of Cancer Terms — National Cancer Institute
  20. What Causes PV? — MPN Research Foundation
  21. Myeloproliferative Neoplasms — Cleveland Clinic Center for Continuing Education
  22. Definition of Philadelphia Chromosome — National Cancer Institute
  23. Oncogenic CSF3R Mutations in Chronic Neutrophilic Leukemia and Atypical CML — The New England Journal of Medicine
  24. Chronic Eosinophilic Leukaemia (CEL) — Leukemia Care
  25. Mastocytosis — National Organization for Rare Disorders

A myMPNteam Member said:

I have been diagnosed with ET, with a high eosinophil count as well, and the only mutation they’ve found it a rare cKIt r888q mutation.

posted about 1 month ago

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Todd Gersten, M.D. is a hematologist-oncologist at the Florida Cancer Specialists & Research Institute in Wellington, Florida. Review provided by VeriMed Healthcare Network. Learn more about him here.
Heather Lapidus Glassner has over two decades of experience in market research. She has conducted social listening and quantitative survey research across a variety of conditions. Learn more about her here.

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