What Causes Acute Lymphocytic Leukemia (ALL)?

Some people with acute lymphocytic leukemia (ALL) have one or more of the known risk factors, but many do not. Even when a person has one or more risk factors, it can be very hard to know if it actually caused the leukemia.

Great progress has been made in understanding how certain changes in the DNA in normal bone marrow cells can cause them to become leukemia cells. The DNA inside our cells makes up our genes, which control how our cells function. We tend to look like our parents because they are the source of our DNA. But our genes affect more than the way we look.

Some genes control when our cells grow, divide to make new cells, and die at the right time:

• Certain genes that help cells grow, divide, or stay alive are called oncogenes.
• Genes that keep cell growth and division under control or make cells die at the right time are called tumor suppressor genes.

Each time a cell divides into 2 new cells, it must make a new copy of its chromosomes (long strands of DNA). This process isn't perfect, and errors can occur that can affect genes within the chromosomes. Cancers (including ALL) can be caused by mutations (changes) that turn on oncogenes or turn off tumor suppressor genes. These types of changes can stop bone marrow cells from maturing the way they normally would, or help the cells grow out of control.

Mutations in many different genes can be found in ALL cells, but larger changes in one or more chromosomes are also common. Even though these changes involve larger pieces of DNA, their effects are still likely to be due to changes in just one or a few genes that are on that part of the chromosome. Several types of chromosome changes may be found in ALL cells:

Translocations are the most common type of chromosome change that can lead to leukemia. A translocation means that DNA from one chromosome breaks off and becomes attached to a different chromosome. The point on the chromosome where the break occurs can affect nearby genes – for example, it can turn on oncogenes or turn off genes that would normally help a cell mature.

The most common translocation in ALL in adults is known as the Philadelphia chromosome, which is a swap of DNA between chromosomes 9 and 22, abbreviated as t(9;22). Many other, less common translocations, can occur as well, including those between chromosomes 4 and 11, t(4;11), or 8 and 14, t(8;14).

Other chromosome changes such as deletions (the loss of part of a chromosome) and inversions (the rearrangement of the DNA within part of a chromosome) are also sometimes found in ALL cells, although they are less common. In many cases of ALL, the gene changes that lead to the leukemia are not known.

Doctors are trying to figure out why these changes occur and how each of them might lead to leukemia. But there are different subtypes of ALL, and even within a subtypes, not all cases of ALL have the same gene or chromosome changes. Some changes are more common than others, and some seem to have more of an effect on a person’s prognosis (outlook) than others.

Inherited versus acquired gene changes

Some people with certain types of cancer have inherited DNA mutations from a parent that increase their risk for the disease. Although this can happen sometimes with ALL, such as with some of the genetic syndromes listed in Risk Factors for Acute Lymphocytic Leukemia (ALL), inherited mutations are not a common cause of ALL.

Usually DNA mutations related to ALL are acquired during the person’s lifetime, rather than having been inherited. They may result from outside causes like exposure to radiation or cancer-causing chemicals, but in most cases the reason they occur isn't clear. Many of these gene changes are probably just random events that sometimes happen inside a cell, without having an outside cause. These changes can build up as we age, which might help explain why ALL in adults gets more common as people get older.