The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 37

44. What is a myeloproliferative neoplasm? Is that what mast cell disease is?

First, let’s pull this term apart.

“Myelo” means marrow, like bone marrow. In this context, it refers to a specific group of blood cells that are made in the bone marrow. These cells are called myeloid or myelogenous cells. These cells all start as one kind of cell called a myeloid progenitor cell. Mast cells and eosinophils are myeloid cells. There are other myeloid cells, too.

“Proliferative” means making lots of cells quickly. In this case, it means making many cells too quickly. When too many cells are made too quickly, the cells are often not made correctly so they don’t work right.

“Myeloproliferative” means making too many myeloid cells very quickly, producing cells that often don’t work right.

“Neo” means new.

“Plasm” means the substance that makes up something living, like what makes up a cell or a tissue. “Plasm” is part of many words used in biology.

“Neoplasm” means the body growing new things, things that don’t belong there. For example, cancers are neoplasms. (Although not all neoplasms are cancers).

Myeloproliferative neoplasm means your body making too many myeloid cells that don’t work correctly.

Speaking generally, any condition where the body makes too many of these myeloid cells when they shouldn’t is a myeloproliferative neoplasm. This means all form of mastocytosis and mast cell tumors (mast cell sarcoma and mastocytoma) are myeloproliferative neoplasms.

However, when people ask if mast cell diseases are myeloproliferative neoplasms, they are usually asking about the WHO (World Health Organization) classification of mast cell disease, which is a little different.

The WHO puts out an exhaustive list of diseases for reference. They group similar diseases together under one category. This list is also revised periodically as new data becomes available or experts request it.

Under the 2008 WHO guidelines, mast cell diseases were classified as myeloproliferative neoplasms along with several other diseases. The other diseases also included in this category make too many myeloid cells too quickly, like essential thrombocythemia, in which the body makes too many platelets.

The mast cell diseases classified as myeloproliferative neoplasms were cutaneous mastocytosis: maculopapular cutaneous mastocytosis (MPCM), diffuse cutaneous mastocytosis (DCM), and solitary mastocytoma of the skin; systemic mastocytosis: indolent systemic mastocytosis (ISM), systemic mastocytosis with associated hematologic disease (SM-AHD), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL); and mast cell sarcoma. Smoldering systemic mastocytosis (SSM) was mentioned as a provisional category rather than a formal category, meaning that the WHO did not agree that this diagnosis was different enough from ISM to warrant its own category. Neither monoclonal mast cell activation syndrome (MMAS) or mast cell activation syndrome (MCAS) were classified anywhere in the 2008 WHO Guidelines as they were not yet recognized by the WHO as diseases.

Last year, the WHO revised the classification of myeloproliferative neoplasms. It removed all forms of mast cell disease from the myeloproliferative neoplasm category and made a different category for mast cell diseases. This was done because the WHO recognized that mast cell diseases differed from the other myeloproliferative neoplasms in specific ways. They also recognized that mast cell activation syndrome has a ton in common with other mast cell diseases even though it’s not a neoplastic disease. (Mast cell activation syndrome is not from the body making too many mast cells).

So all mast cell diseases were put together. In the new category, the following mast cell diseases were included: cutaneous mastocytosis: maculopapular cutaneous mastocytosis (MPCM), diffuse cutaneous mastocytosis (DCM), and solitary mastocytoma of the skin; systemic mastocytosis: indolent systemic mastocytosis (ISM), systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL); mast cell sarcoma; monoclonal mast cell activation syndrome (MMAS); and mast cell activation syndrome (MCAS).

Explain the tests: Complete blood count (CBC) – High red cell count (Part 3)

A number of conditions can cause high red blood cell count.  This is called polycythemia.  Red cells are responsible for bringing oxygen from the lungs to the tissues. If the blood is getting less oxygen than normal, the bone marrow will produce more red cells to compensate.  Excessive release of erythropoietin, a molecule that triggers red cell production, can also cause high red blood cell count.  Additionally, changes in amount of fluid in the blood stream can artificially alter red blood cell and hemoglobin levels.

Normal range for red blood count:

  • Adult women: 3.9-5.0 million cells/µL
  • Adult men: 4.3-5.7 million cells/µL

Reasons for making too many red blood cells:

  • High levels of erythropoietin, a molecule that tells the bone marrow to make red cells
  • Lower levels of oxygen in blood stream
  • Neoplastic conditions
  • Relative polycythemia, in which reduction of blood volume causes an artificial increase in red blood cells

Some conditions that cause lower oxygenation of the blood, triggering polycythemia:

  • Lung diseases, such as COPD, sleep apnea and pulmonary fibrosis.
  • Heart conditions, such as congestive heart failure.
  • Carbon monoxide poisoning.
  • Hemoglobin defects, such as 2,3-BPG deficiency, which causes hemoglobin to hold onto oxygen too tightly.
  • Lengthy stays at high altitude.

Some conditions that cause elevated erythropoietin:

  • Poor blood flow to the kidney, such as in narrowing of the renal artery, hydronephrosis and kidney cysts. The body interprets as low oxygenation.
  • Chuvash polycythemia, which causes overactivity of the erythropoietin gene.

Some neoplastic conditions that cause excessive proliferation of red cells:

  • Polycythemia vera. This myeloproliferative disorder (MPN) is strongly associated with the JAK2 V617F mutation.
  • Cancers such as renal cell carcinoma and adenocarcinoma.

Situations that cause artificially high red blood cell count:

  • Hypovolemia, from dehydration, alcoholism, obesity, smoking or third spacing.
  • Use of some diuretics.

Some medications that cause secondary polycythemia:

  • Anabolic steroids
  • Testosterone

 

Special notes on high red cell count for mast cell patients:

  • Polycythemia vera is a myeloproliferative neoplasm like systemic mastocytosis. It is a common comorbidity for patients with SM-AHNMD.  Some SM patients are positive for the JAK2 V617F mutation without having polycythemia vera.
  • Third spacing (fluid from the blood stream becoming trapped in the tissues) occurs in many mast cell patients as a regular symptom, as well as during anaphylaxis. This can cause the red cell count to appear artificially high.

What do all these words mean? (Part 1)

What is a neoplasm?

A neoplasm is an abnormal growth of cells. Systemic mastocytosis is a neoplasm because your body makes too many mast cells. Cancers are all neoplasms, but not all neoplasms are cancers. SM is not cancer.

 

What is a myeloproliferative neoplasm (MPN)?

Myelo- means “related to granulocytes”, cells that store chemicals in granules. Mast cells are a type of granulocyte.

Proliferative means “cell growth”.

So together you have “growth of too many granulocytes”.

 

What are receptors?

Receptors are proteins on the outside of cells. They have very unique and specific shapes, but it is easier to think of them as being shaped by cups. Only very specific molecules fit into these cups. When the molecule is in the receptor, the cell knows to do something. What this something is varies a lot from receptor to receptor.

For example, when an IgE antibody binds to the IgE receptor on a mast cell, the mast cell degranulates. However, not any molecule would be able to bind in the IgE receptor and cause this action.

 

What are antibodies?

These are large proteins that help the immune system identify and destroy things like bacteria and viruses. Sometimes your body mistakenly makes antibodies to things inside the body. This causes autoimmune disease.

In labs, antibodies are very useful. There are ways to make antibodies to almost anything in the lab. Using these lab made antibodies, scientists are able to test for specific structures that tell us what cells are present in a sample and how the cells are working.

 

What are immunoglobulins?

They are the same as antibodies.

 

What does CD mean? Like in CD117?

CD means “cluster of differentiation”. This means that it is a protein or group of proteins on the surface of a cell that is recognized by an antibody. This means that in a lab, if I use an antibody called “ABC123” and it binds to a specific protein on the outside of cells, that protein will be called “CD-ABC123”.

Over time, as we learn more about “CD-ABC123”, we may realize that this protein is made by a gene called “Wow”. So some people will call it “Wow” and some will continue to call it “CD-ABC123”, which can be confusing. Generally speaking, scientists who work with antibody testing usually use the “CD-ABC123” name and doctors use the “Wow” name. However, both names are still correct.

Receptors are often given “CD” names, but not all “CD” molecules are receptors. Some “CD” molecules are on the outside of cells to do other things, like help cells stick to other cells.

 

What is CKIT?

CKIT is a receptor that is found on all mast cells, whether or not a person has mast cell disease. The CKIT receptor is also called CD117. They are the same thing. CKIT is sometimes also called KIT. They are also the same thing.

The molecule that fits in the CKIT receptor is called stem cell factor (SCF). When SCF binds the CKIT receptor, it tells the mast cell to stay alive much longer than it is supposed to. It also starts a process that tells mast cells to make more mast cells.

 

CKIT (CD117) is only found on mast cells?

No, other normal cells have CKIT (CD117) on their surface. Epithelial cells in the skin, breast and some parts of the brain express CD117. Some stem cells in the bone marrow and melanocytes also express CD117. Smooth muscle and fibroblasts do not express CD117. This is important because smooth muscle and fibroblasts are often found close to the cells we might be looking for that may be positive for CD117.

However, when found on cells that don’t normally express CD117, it can be a sign of cancer – but ONLY if these cell types don’t normally have CD117 on their surfaces. Examples of cancers that express CD117 include angiosarcoma and Ewing sarcoma.

Mast cell mutations: JAK2 and myeloproliferative neoplasms

Janus kinase 2 is also a tyrosine kinase like CKIT, but it is not a receptor on the outside of the cell. JAK2 is a helper protein that helps other molecules to send signals. It also affects the signaling of many clinically important molecules, like interleukin 3, interleukin 5, interleukin 5, interferon gamma, erythropoietin, thrombopoietin, growth hormone and prolactin. These molecules are involved in cell proliferation and the inflammatory response.

JAK2 mutation V617F seems to make hematopoietic cells more responsive to growth factors, causing excessive proliferation. JAK2 V617F is used as a marker for some Philadelphia negaitve myeloproliferative neoplasms (Ph- MPN), which include essential thrombocythemia (ET), an indolent disease in which too many platelets are produced; polycythemia vera (PV), in which too many red cells are produced; and myelofibrosis (MF), in which bone marrow is replaced with connective tissue that cannot make blood cells. JAK2 V617F is present in 40-50% of ET cases, 95% of PV cases, and 60% of MF cases.

In multiple studies, the frequency of JAK2 mutations in SM has ranged from 0-20% depending on the patient group. However, multiple studies have found a frequency of 4.2-5%, which is the generally accepted figure. JAK2 mutation is a strong predictor of myeloproliferative neoplasm but not necessarily of mastocytosis. However, where present in SM patients, it indicates a higher probability of developing another MPN.

In the control group of one study, 10 ISM patients without another myeloprofilerative neoplasm were negative for JAK2 mutation, and 15 MF patients without SM were negative for CKIT mutation. In the patient group, five people had both CKIT+ SM and MF. In four patients, the JAK2 V617F mutation was present. In the four patients with the JAK2 V617F mutation, it was found not only in the myelofibrosis cells (CD15+ myeloid cells), but also in the mast cells. In two of the patients, the CKIT mutation was found in the CD15+ myeloid cells of two patients. The data suggests that the JAK2 mutation may occur before the CKIT mutation in patients who have both SM and an associated hematologic disorder.

One study looked extensively at other mutations present in various types of CKIT+ systemic mastocytosis. The patient group was composed of 39 people, with 10 having ISM, 2 SSM, 5 SM-AHNMD, 15 ASM and 7 MCL. Only 2 patients out of the group were positive for JAK2 mutation. One patient had MCL, the other had SM-AHNMD. Both also had another myeloproliferative neoplasm (in the case of the SM-AHNMD patient, it was MDS.) This study found that presence of at least one other mutation in addition to CKIT D816V was associated with poorer prognosis, although presence of JAK2 V617F was not specifically identified as causing shorter lifespans.

 

References:

Schwaab, Juliana, et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood 2013, 122 (14): 2460-2466.

Soucie, Erinn, et al. Molecular basis of mast cell disease. Molecular immunology 2015, 63 (1): 55-60.

J. Molderings. The genetic basis of mast cell activation disease – looking through a glass darkly. Critical Reviews in Oncology/Hematology 2014.

Sotlar, Karl, et al. Systemic mastocytosis associated with chronic idiopathic myelofibrosis. J Mol Diagn Jan 2008; 10(1): 58-66.