Understanding RUNX1-FPD

RUNX1 is the name of a gene that encodes the instructions for making a protein, which is also called RUNX1 ("RUNX1" is italicized when referring to the gene itself, but not italicized when discussing the protein).

Every person has two copies of the gene RUNX1, and it is found on chromosome 21 in our DNA.

RUNX1 protein is like a traffic cop for some of our genes; it tells the genes when to start working or stop working. RUNX1 is important for making sure our blood cells are healthy and capable of doing their job properly.

Patients with RUNX1-FPD were born with a permanent change (called a “variant”) in the DNA of only one of their 2 RUNX1 gene copies. This can cause either no RUNX1 protein to be made or a RUNX1 protein that doesn't work properly.

We need the right amount of RUNX1 protein to make megakaryocytes, which are the cells responsible for creating platelets, the part of our blood that helps it clot to stop bleeding.

People with RUNX1-FPD usually have low platelet counts, and their platelets don't work as they should. This condition can also increase their risk of developing blood cancer, as we'll explain below.

Thrombocytopenia means having a low number of platelets in your blood. Each lab has its own reference range of what's normal, but generally, a healthy platelet count is between 150,000 and 450,000 platelets per microliter of blood.

However, in some people with RUNX1-FPD, their platelet count might look normal, which can make it hard to spot the condition.

Having a low platelet count can lead to more bleeding, especially bruising that looks like big purple spots (called 'purpura') or tiny red dots (called 'petechiae') even without a big injury. It can also cause nosebleeds, gums that bleed, heavy periods for girls and women, and more bleeding during surgery.

The most serious problem is when there's bleeding inside the brain, which can happen even if it the head isn’t hit hard.

Not right now, though scientific development may make it possible one day.

There's a technology called CRISPR, which is like a gene-editing tool. Scientists are using it to work on other blood diseases like sickle-cell anemia and thalassemia.

We are cautiously optimistic that this technology could be used one day to correct RUNX1 variants in blood stem cells of RUNX1-FPD patients. Our caution is due to the risks of the gene editing process, which could cause other unintended errors in the DNA. This could lead to harmful health problems.

Additionally, the process of removing and then re-transplanting blood stem cells (before and after gene editing) comes with its own major challenges and health risks.

RRP continues to support important scientific research that will help determine if gene editing can be helpful for RUNX1-FPD while closely watching gene editing technology improvements in hopes that risks are one day further reduced.

Mostly, yes. People with RUNX1-FPD often have low platelet levels, and the platelets they do have don't work well, which can lead to problems like nosebleeds, extra bleeding during small surgeries, and easy bruising.

How much this affects your life depends on how low your platelets are. You don't need to worry about it every day, but it's important to see a specialized doctor called a hematologist who knows about platelet disorders. They can help you learn how to take care of yourself best, monitor for any concerns at home and set up a plan for you two to monitor your health with specific lab tests.

Here are some things you might need to do:

• Avoid aspirin and some pain medicines like ibuprofen.

• Keep your teeth and gums healthy.

• Learn how to handle nosebleeds and know the signs of bleeding in your brain.

• If you're female, manage heavy periods with the help of a gynecologist.

• If you need surgery, make sure your surgeon and hematologist talk to each other for the best care.

There's a risk of getting blood cancer because of RUNX1-FPD. This risk is between 35-50 percent*. Also, some people with this condition might have other problems like psoriasis, allergies, or arthritis. Researchers and RRP are studying this to better understand how frequent these inflammatory-related conditions occur and why.

Living with a higher risk of cancer can of course be tough. We at RRP have many ways to help process this with you including a virtual peer support group, annual patient meetings, informal online discussions, and an updated list of research you can be a part of so that you know you’re helping make progress toward a cancer prevention.

* According to a 2014 review of 11 FPD/AML papers, "Distinct FPD/AML families have varying risks of progression to myeloid malignancy (range, 11%-100%; median, 44%).” Godley, Lucy A., “Inherited Predisposition to Acute Myeloid Leukemia.”

Doctors use genetic tests to check if you have this condition. First, your hematologist/oncologist will talk to you about any symptoms you have and your family history. Then, depending on your answers they may ask for a sample of your blood, skin or even hair/nails to check for genetic changes in your RUNX1 gene.

Usually, people with RUNX1-FPD have low platelets (which help with blood clotting), and/or they have platelets that do not work well. This can make you bruise and bleed more easily, and girls and women can have really heavy periods. Sometimes, even if your platelet count is in the normal range, your platelets may still not work as well as they should.

If you think you might have this condition and have not been able to find a healthcare provider to help you, please reach out and we can help. For example, there's a study at the National Institutes of Health (NIH) that can help check for it with little to no cost to you. You can learn more about it here.

There are also many genetic counselors available to discuss your history and help you determine if you should be tested. You can find one in the U.S. and Canada through the National Society of Genetic Counselors: Home (nsgc.org). If you are outside of the U.S. and Canada, you will want to ask your health care team or a local clinic for a recommendation.

You may also reach out to us and we can do our best to find experts in your area.

Some health systems and insurance systems across the world will cover the cost of genetic testing, especially if there's cancer in the family. If you and your doctor think you might have RUNX1-FPD, and you have trouble getting testing that you can afford, you may want to consult a genetic counselor who can help you write an appeal letter.

Alternatively, you can get a genetic test for little to no cost as part of the National Institutes of Health’s (NIH’s) RUNX1-FPD Clinical Research Study. The study is looking at people and families who might have RUNX1 variants that cause RUNX1-FPD. You can find out more about it here.

RUNX1-FPD can affect anyone, no matter where they come from or what their background is. It is thought of as a rare condition, but it is more common than we originally thought, especially as more people learn about it and get tested. In the United States, we think there could be up to 18,000 people with RUNX1-FPD.

RUNX1-FPD is a genetic disease, and it is known as 'autosomal dominant.' That means the if one of your parents has a RUNX1 variant, then there's a 50-50 chance they could pass it on to you.

It does not matter if your brothers or sisters have it or not; each of you has the same chance of getting it. If one of your parents has a RUNX1 variant but you do not inherit the RUNX1 variant from that parent, you won't have the condition AND you cannot pass it on to your kids.

There are some individuals who are the first in their family to have a RUNX1 variant, meaning they did not inherit the variant but rather the genetic change happened randomly while in womb. It is termed by medical professionals as a ‘de novo’ variant, because it is new in the family. This is how a RUNX1 variant starts in a family.

Developing a blood cancer is a complicated process and won’t happen in every person with RUNX1-FPD (35-50% of people will develop a blood cancer). Scientists have learned that the patients who develop blood cancer collect new cancer-causing variants in their blood cells, called somatic (or “acquired”) variants which are new changes (mutations) in your genes that happen over time.

What is unique is that people with RUNX1-FPD seem to get these additional variants faster than people without a RUNX1 variant. Scientists are studying which of these additional variants are the most dangerous and signal that a RUNX1-FPD patient may be developing a blood cancer. It is complicated because all humans collect new variants in our blood over time, we don’t know which variants will cause cancer. Learn more about those research studies here.

There are some things you can do to limit your risk of getting blood cancer if you have RUNX1-FPD. These include:

• Keep a healthy weight.

• Eat a balanced and anti-inflammatory diet.

• Wear sunscreen.

• Do not smoke.

• Limit or avoid alcohol.

• Avoid exposure to radiation, benzene, insecticides, pesticides, and harmful chemicals.

• Stay active and get regular exercise.

• Manage stress through things like meditation and breathing exercises.

Also, it's a good idea to get a blood test from your regular doctor or hematologist at least once year to see if anything is changing. Depending on your age, your family history and other clinical findings your doctor may ask to check your blood more frequently. You may also need regular bone marrow biopsies.

There are no specific treatments or supplements that we know to stop RUNX1-FPD from turning into blood cancer, but it is the mission of RRP to find these. For example, we're looking into medicines that might help the RUNX1 gene work better and prevent the disease from getting worse. We continue to share any new information scientists learn through emails and newsletters, and you can sign up here if you would like to receive these.

For individuals with RUNX1-FPD, the most frequently diagnosed blood cancers include acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Additionally, cases have been observed where individuals develop other forms of leukemia and blood-related cancers, such as acute lymphoblastic leukemia (ALL), T-cell Acute Lymphoblastic Leukemia (T-ALL), chronic myelomonocytic leukemia (CMML), Non-Hodgkin’s lymphoma, and myeloproliferative neoplasm (MPN), highlighting the broad spectrum of hematologic malignancies associated with RUNX1-FPD.

AML is a type of blood cancer where abnormal white blood cells grow too fast in the bone marrow, and it can make you feel really sick, like you have the flu. MDS is a bone marrow problem where the body cannot make enough healthy blood cells, which can lead to infections and bleeding problems. ALL is another kind of leukemia that affects either T cells or B cells. Lymphomas are cancers that start in the lymph nodes.

If you want to learn more about these types of cancer, you can check out the Leukemia and Lymphoma Society website. They have a lot of information to help you understand them better.

Originally, the disorder was called familial platelet disorder with predisposition to AML (FPD/AML) because the first people scientists described with the disease had a family history of low platelets and AML. At that time the causative gene, RUNX1, hadn’t been discovered. Later scientists decided to rename it to FPDMM (familial platelet disorder with myeloid malignancies) because more families had been discovered with blood cancer and family member developed not only AML but other blood cancers, like myelodysplastic syndromes (MDS).

We now know that other parts of the blood system beyond myeloid cells can become cancerous, including lymphoid cells. RUNX1-FPD families are susceptible to many different types of blood cancer. Finally, once the causative gene RUNX1 had been discovered it made sense to refer to the disease as RUNX1 familial platelet disorder so that healthcare providers know that genetic testing is necessary to diagnose the disease and to be able differentiate patients and their families from the many other platelet disorders and hereditary cancers. Throughout the scientific literature you will find all the names used.