Extra or Missing Chromosomes

Are you born with the Philadelphia chromosome? If not, how do you get it?

-A curious adult from California
January 30, 2009

People aren't born with a Philadelphia chromosome. It happens because of a mistake our bodies can make later in life. The mistake is that a piece of chromosome 9 sticks to a piece of chromosome 22.

This mistake leads to a very serious blood cancer called "chronic myeloid leukemia," or CML. In fact, 85-90% of people with CML have this chromosome.

To understand why this happens and why it can cause problems, we need to explore what a chromosome is and what it does. We also need to look at how a cell divides.

Chromosomes Have Information for Running a Cell

So what is a chromosome, anyway? "Chromosome" is really just a fancy word for "long, long piece of DNA."

DNA is the stuff your genetic information is made of. It is like the letters in the words of the instructions for building you. Part of these instructions comes in sections of DNA called genes. Each gene is a recipe for making a certain protein. And a protein is the thing that does a very specific job in a cell.

You may have heard of some proteins our body makes. Insulin is a protein important to people with diabetes. It helps to control the levels of sugar in your bloodstream. And hemoglobin is a protein that everyone has in their red blood cells to help carry oxygen to all parts of your body.

We have over 21,000 genes all making different proteins. For a cell to work right, these genes need to all be making the right protein, in the right place, at the right amount, at the right time. These instructions can sometimes develop a glitch when a new cell is made.

Chromosomes Sometimes Get Changed When Copied

Many cells in your body need to make new copies of themselves to replace worn-out cells. Cells make new cells by doubling in size and then splitting in half. The end result is two cells. During this process, a cell's DNA is copied and divided evenly between the two new cells.

Very rarely the cell makes a mistake in all this copying and dividing. Sometimes, this mistake is small enough that it's not a problem. In fact, you probably have some places where your DNA is copied differently in various cells and your genes still work fine!

Sometimes, though, the mistake is big, like with the Philadelphia chromosome. These big mistakes sometimes lead to big problems like cancer.

How the Philadelphia Chromosome Leads to CML

A big DNA mistake can lead to cancer when it affects certain genes. When some genes are on when they shouldn't be, they can turn a cell cancerous. Other genes can get shut off and cause cancer. And still others can be turned up or down and cause cancer.

Cells control when and how much a protein gets made through certain bits of DNA on the chromosome near the gene. Let's call these "control elements."

You can think of control elements like light switches. Let's say you have a light in your hallway that you want to be on all the time. To do this, you get a light switch that is always in the on position. Now what if you accidentally wired your house so that the hallway light switch controlled your bedroom's light? You'd end up with the light always on in your bedroom and very little sleep!

This is kind of like what is happening with the Philadelphia chromosome. In this case, two genes end up getting stuck together to make a Frankenstein sort of protein. The two genes are called Bcr and Abl.

This new Bcr-Abl protein can still carry out the job that the normal Abl protein did before it became the "Frankenstein" Bcr-Abl. However, the real problem is that the chromosome's wiring is now all messed up. In our hallway and bedroom light example, Bcr is the light bulb in the hall and Abl is the light bulb in the bedroom. The Abl gene usually has an on/off switch like the bedroom light and the Bcr gene is always on.

When Abl was attached to Bcr, it was now put under control of Bcr's control element. The chromosome is rewired so that Abl is always on.

And this is much worse than a light that is always on in the bedroom! Abl is normally under tight control because its job is to tell a cell when to divide. You definitely don't want it telling a cell to divide when it shouldn't, because that is one way for a cell to turn cancerous. But that is exactly what happens with the Philadelphia chromosome.

The Bcr-Abl protein, which can also tell a cell when to divide, is now always on. So the blood cells divide when they shouldn't. They start making way too many copies of themselves and you end up with CML.

A Treatment for CML

It is tricky to figure out why most cancers happen. We know that the cancer came from DNA damage. We just don't know where the DNA was damaged.

Usually it doesn't even help if two cancers come from the same tissue. For example, all prostate cancers don't come about for the same reason. Nor do most blood cancers. This can make treating cancer difficult because how a cancer developed affects what medicines will work best.

This is where CML is different. As I said earlier, around 85-90% of people with CML have the Philadelphia chromosome. If doctors can come up with a way to deal with the Bcr-Abl protein, then the treatment should work in most cases of CML.

And scientists have done just that. In the 1990s, scientists developed a drug called "imatinib" that keeps Bcr-Abl from working in these blood cancer cells. Imatinib has increased the length of time patients with CML can survive with the disease, and seems to work much better than previous treatments.

Mark McElwain

The Philadelphia chromosome
is formed when a piece
of chromosome 9 sticks to
a piece of chromosome 22.

Chromosomes are made of DNA.
DNA carries the instructions for
making proteins.