Understanding the Genetics of CML and Difficulty of Identifying a Cause

Chronic myeloid leukemia is an acquired disease from a gene mutation and is neither inherited (passed down from generation to generation) nor contagious.

Acquired vs. Inherited Genetic Mutation

Dr. Eric Winer, clinical director of adult leukemia at Dana-Farber Cancer Institute, told SurvivorNet that there’s a very big difference between an acquired mutation and a mutation someone is born with (inborn).

“An inborn mutation means it’s something that you’re gonna pass down to your children, something like blue eyes or height or some, some other type of a physical or even non-physical features. Whereas this particular gene mutation (that causes CML) is something that’s acquired,” Dr. Winer explained.

What is the Philadelphia Chromosome?

The Philadelphia (Ph) chromosome is present in the blood cells of 90% of people with CML. Let’s help you understand what the Ph chromosome is.

According to the National Cancer Institute, chromosomes are structures found inside the nucleus of a cell. A chromosome is made up of proteins and DNA organized into genes. People normally have 46 chromosomes, divided into 23 pairs, in each cell. One of each pair of chromosomes comes from your mother, and the other pair comes from your father.

The development of an abnormal chromosome

CML occurs when a cell in the bone marrow undergoes a breakage of two chromosomes (chromosomes 9 and 22), which then fuse to form a characteristic abnormal chromosome, called the Philadelphia chromosome (named for the city in which it was first identified).

"What happens [in CML] is there is a cross in your chromosomes, so there cross between chromosome 9 and chromosome 22 where a piece of chromosome 9 ends up on chromosome 22 and a piece of chromosome 22 ends up on chromosome 9 … when you have that chromosome switching, it puts two genes next to each other,” Dr. Winer explained. "Those two genes are called BCR and ABL." This gene product eventually leads to the overproduction of cells seen in CML.

The abnormal chromosome creates a new gene

The chromosome fusion causes an exchange of genetic information in which two separate genes, BCR and ABL1, are joined together. The resultant abnormal gene, called BCR:ABL1, causes bone marrow cells to produce an abnormal protein (the BCR:ABL1 tyrosine kinase), which stimulates CML cells to grow and survive better than normal blood cells. If you want to know more about the BCR-ABL1 testing, make sure to check this information SurvivorNet has put together about it.

Summarizing, this is how the mutation occurs:

• The BCR gene is normally on chromosome number 22.
• The ABL gene is normally on chromosome number 9.
• The BCR-ABL mutation happens when pieces of BCR and ABL genes break off and switch places.
• The piece of chromosome 9 that breaks off includes part of the ABL gene. When this piece moves over to chromosome 22, part of the ABL gene attaches to the BCR gene. The merged gene is called the BCR-ABL fusion gene.
• The changed chromosome 22, which contains the BCR-ABL gene, is called the Philadelphia chromosome.

What causes this Mutation?

“It’s very difficult to study how something occurs when you don’t know how it occurs,” Dr. Winer explained. “And so with so many different environmental factors, with so many different external forces that go on along with somebody’s individual genetics, it’s very hard … to pinpoint how this one particular mutation came about. As of right now, we don’t know how it comes about. And looking at things through a number of different studies and lenses, we haven’t come up with any definitive cause.”

“I am very definitive when I speak to my patients in saying there is nothing that you did that brought this on yourself” – Dr Winer

Although the reason behind this mutation remains unknown, some scientific data support that the following risk factors may increase your chances of getting CML, these include the following:

• Age the older you are, the higher your chances
• Gender Men are more susceptible to CML
• Exposure to radiation

Signs and Symptoms

The symptoms of chronic myeloid leukemia are often vague and often, patients do not have any symptoms. A patient who is unaware that they have the disease might think they're "just not feeling in tiptop shape." Also, many CML symptoms are similar to those of other illnesses.

"When the white blood cells go up, what sometimes will happen is … patients come in anemic, they come in very fatigued, tired, decreased exercise tolerance, unable to do things that they normally do," Dr. Winer explained. "Sometimes they also come in with infections as well because the white cells that they're making aren't normal white cells."

When symptoms do occur, they can include:

• Feeling tired (fatigue)
• Easy bleeding and easy bruising
• Unintentional weight loss
• Shortness of breath with minimal activity
• Fever
• Excessive sweating, especially at night
• Feeling full when you have not eaten much
• Enlarged spleen (felt as a mass under the left side of the ribcage)

Common Treatments

"Once diagnosed, patients with CML are treated with a class of pills called tyrosine kinase inhibitors (TKIs)," Dr. Jay Yang, hematologist, medical oncologist, and leader of the Hematology Oncology Multidisciplinary Team at the Barbara Ann Karmanos Cancer Institute, told SurvivorNet. "These are targeted medications specifically designed to kill the leukemia cells."

In many cases, treatment with TKIs is incredibly effective. "It's possible to have a treatment-free remission from CML after five years of TKI. In more than 50% of patients, the disease will not recur,” added Dr. Frances Arena, medical director at NYU Langone Arena Oncology and Integration.

In cases where patients stop responding to TKIs or have a relapse, other treatments may be utilized, including stem cell transplant.

Here is a breakdown of the treatment options for CML:

• Targeted Treatment: For most people, CML is treated with an oral medication, called a tyrosine kinase inhibitor (TKI). The rates of progression have reduced significantly from over more than 20% in the pre-TKI era to less than 5% now, largely due to refinements in CML therapy and response monitoring. This medication blocks the effects of BCR-ABL1 (the abnormal protein found in people with CML). Though most patients with CML have a normal quality and duration of life with TKI therapy, some patients progress to accelerated phase. The most common TKI medications for CML are:
  • Imatinib mesylate (brand name: Gleevec)
  • Dasatinib (brand name: Sprycel)
  • Nilotinib (brand name: Tasigna)
  • Bosutinib (brand name: Bosulif)
  • Ponatinib (brand name: Iclusig)
  • Asciminib (brand name: Scemblix)
• Chemotherapy: These are drugs that carry toxic substances that inhibit the cancer cells. These are mostly used when TKIs aren't effective, or they cause intolerable side effects (ex. hydroxycarbamide).
• Stem cell transplantation: Also called bone marrow transplantation, this is usually used after the disease stops responding or relapses during treatment with a TKI. SurvivotNet has put together more information on this topic to help you or a loved one should a diagnosis arise: Stem Cell Transplant for Chronic Myeloid Leukemia: What Do You Need to Know?

Sometimes the CML cells are tested to see if they have genetic changes (mutations) that may mean that a certain TKI is more or less likely to work.

Some patients with CML develop a gene change called the T315I mutation that keeps most of the TKIs from working.  Patients with this mutation may be treated with Ponatinib (brand name: Iclusig) or Asciminib (brand name: Scemblix) and are generally encouraged to consider transplantation.

Questions to Ask Your Doctor

• Should my close family be tested?
• Can I pass down these genes to my children?
• What do the BCR-ABL results mean?
• What treatment options are available for me?
• Should I get a second option?

Learn more about SurvivorNet's rigorous medical review process.

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