Chronic myeloid leukemia (CML) is caused by a specific genetic abnormality: a swap of DNA between chromosomes 9 and 22. This swap, called a translocation, creates an abnormal shortened chromosome 22 known as the Philadelphia chromosome. The Philadelphia chromosome produces a faulty protein that forces white blood cells to multiply uncontrollably, and its presence is so central to the disease that CML cannot be diagnosed without it.
The Philadelphia Chromosome
Every cell in your body contains 23 pairs of chromosomes, the structures that hold your DNA. In CML, a piece of chromosome 9 breaks off and attaches to chromosome 22, while a piece of chromosome 22 moves to chromosome 9. Scientists describe this as a “balanced translocation” because the total amount of genetic material stays roughly the same; it’s just in the wrong place.
This swap is not something you’re born with. It happens during your lifetime in a single blood-forming stem cell in the bone marrow. No one knows exactly what triggers it. Once it occurs, that one altered cell begins producing descendants that all carry the same defect, gradually crowding out normal blood cells.
How the Swap Creates a Dangerous Protein
The translocation fuses two genes that normally sit on separate chromosomes. A gene called BCR on chromosome 22 merges with a gene called ABL1 on chromosome 9, creating a hybrid gene: BCR-ABL1. This fused gene acts as a blueprint for a protein that the body was never meant to produce.
The normal ABL1 protein is a type of enzyme called a tyrosine kinase. It transfers chemical signals inside cells by attaching small energy molecules to other proteins, but it only does this when the cell needs it. The BCR-ABL1 fusion protein, by contrast, is stuck in the “on” position permanently. It binds the cell’s energy currency (ATP) and continuously fires off growth signals through multiple pathways inside the cell. The result is threefold: cells divide when they shouldn’t, they resist the normal self-destruct signals that would eliminate damaged cells, and they lose the ability to mature properly.
This is the core abnormality driving CML. Immature white blood cells accumulate in the bone marrow and spill into the bloodstream because the BCR-ABL1 protein won’t stop telling them to grow.
What Happens Inside the Bone Marrow
CML begins in a very early type of blood-forming stem cell in the bone marrow. These stem cells are supposed to mature into various types of adult blood cells, including red blood cells, platelets, and different white blood cells. When the BCR-ABL1 fusion gene is present, this maturation process stalls partway through. The cells get stuck in an immature state and keep multiplying instead of developing into functioning blood cells.
Over time, this creates a growing population of leukemia stem cells that sustain the disease. These leukemia stem cells can also pick up additional genetic mutations beyond the original Philadelphia chromosome, which is what drives the disease to progress into more dangerous phases.
The Three Phases of CML
CML progresses through stages defined by the percentage of immature cells (called blasts) in the blood and bone marrow. In the chronic phase, blasts make up less than 10% of cells. Most people are diagnosed in this phase, and the disease is relatively stable. In the accelerated phase, blasts rise to 10% to 19%, and the disease becomes harder to control. In the blast phase, blasts reach 20% or higher, and the disease behaves more like an aggressive acute leukemia.
Additional chromosomal abnormalities can signal that progression is underway. High-risk changes include gaining an extra copy of the Philadelphia chromosome, losing chromosome 7, or acquiring extra copies of chromosomes 8, 19, or 21. A high percentage of basophils (a type of white blood cell) in the blood, specifically 20% or more, is another warning sign.
How the Abnormality Is Detected
Three main laboratory methods can identify the Philadelphia chromosome. Standard chromosome analysis (karyotyping) looks at the chromosomes under a microscope and can spot the shortened chromosome 22, but it occasionally misses cases. A technique called FISH (fluorescence in situ hybridization) uses fluorescent probes that light up when BCR and ABL1 are fused together. FISH detects the fusion in essentially 100% of positive cases and works even when the translocation is too subtle for a microscope to catch.
The third method, RT-PCR, detects tiny amounts of the BCR-ABL1 genetic material in blood samples. It is extremely sensitive, reaching about 97% detection in positive cases, but can occasionally produce false-positive results. In practice, doctors often use more than one test to confirm the diagnosis and then rely on RT-PCR to monitor how well treatment is working over time.
Why This Abnormality Made CML Treatable
Because CML is driven by a single, well-understood protein, it became one of the first cancers to be treated with a targeted drug. Tyrosine kinase inhibitors (TKIs) work by physically blocking the spot on the BCR-ABL1 protein where ATP normally binds. Without access to ATP, the fusion protein can’t relay its growth signals, and the leukemia cells stop multiplying.
The first of these drugs transformed CML from a disease with a median survival of three to five years into one where most people in the chronic phase can expect a near-normal lifespan. Several newer TKIs exist for patients whose disease doesn’t respond to the original drug, often because the BCR-ABL1 protein has developed small mutations in its binding site. The treatment strategy is guided by repeated measurement of BCR-ABL1 levels in the blood, with the goal of driving the fusion gene’s activity as low as possible.
CML-Like Disease Without the Philadelphia Chromosome
A small number of people develop a condition that looks like CML under the microscope but lacks the Philadelphia chromosome entirely. This is classified separately as atypical CML (sometimes called MDS/MPN with neutrophilia in newer classification systems). It is a distinct disease with different genetics and a different prognosis.
Atypical CML involves mutations in other genes. The most common is SETBP1, found in roughly a third of cases. This gene normally helps regulate DNA replication, and mutations cause it to malfunction. Another gene, ETNK1, is mutated in about 13% of atypical CML cases. Mutations in genes involved in cell signaling (such as NRAS, KRAS, and CSF3R) and genes that regulate how DNA is read and maintained (ASXL1, TET2, SRSF2, EZH2) also appear frequently. Because atypical CML lacks the BCR-ABL1 target, the tyrosine kinase inhibitors that work so well for true CML are not effective against it, and treatment options are more limited.
The critical takeaway: CML in its classic form is defined by the Philadelphia chromosome and the BCR-ABL1 fusion protein. This single genetic abnormality is both the cause of the disease and the target that makes it treatable.