The Story of ABL1 and ABL2


The Story of ABL1 and ABL2

A gene's head is lopped off and replaced with another, creating an out-of-control chimera.

ABL1/2 Mutations at a Glance
  • ABL1/2 mutations may appear in chronic myeloid leukemia (CML), melanoma, breast cancer, and advanced colorectal and pancreatic cancers, as well as in about 10 percent of non-small cell lung cancers (NSCLC).

  • When ABL2 works properly, it plays a crucial role in how cells are structured and how they move around the body. Current research suggests that mutated ABL2 genes may play a role in the invasiveness of cancer, and suggests that these mutations promote metastasis in breast cancer.

  • Testing for an ABL2 mutation requires a tumor sample taken during biopsy.

  • ABL mutations in cancer are promising drug targets. The ABL inhibitor imatinib (Gleevec) is already used to treat patients with CML. A recent study showed that lung cancer cells with ABL mutations were susceptible to ABL inhibitors. And one analysis showed that ABL played a role in the metastasis of most invasive ER negative cancers.

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This gene is also known as:

ABL1: ABL1, ABL Proto-Oncogene 1, V-Abl Homolog 1, C-ABL1, P150, JTK7 ABL2: ABL2, ABL Proto-Oncogene 2, ABLL, ARG, V-Abl Homolog 2, C-Abl Oncogene 2

In 1981, Dutch biologists Nora Heisterkamp and John Groffen moved with their two Siamese cats to Frederick, Maryland. The pair rented a house with a hideous orange carpet and no furniture -but Heisterkamp and Groffen didn’t care about interior decorating. They were working about 80 hours a week at the National Cancer Institute, investigating a gene that became known as ABL1.

Scientists had already found a potential link between ABLr and cancer in mice. When part of the mouse version of the ABLr gene was incorporated into a virus’s genome, mice infected with that virus developed cancer. But researchers hadn’t yet found the human version of the gene or determined whether it caused cancer in people. In pursuit of an answer, Heisterkamp and Groffen isolated part of the human ABLr gene and worked with UK researchers to narrow down its location in the genome. It was on chromosome 9.

That number was significant. Two decades earlier, scientists in Philadelphia had discovered that one of the chromosomes in patients with chronic myeloid leukemia (CML) was unusually small. This stubby bit was named the “Philadelphia chromosome.” In 1973, another researcher found evidence suggesting that the abnormality resulted from a swap of genetic material. In CML patients, a segment of DNA on chromosome 22 jumped to chromosome 9, and likely vice versa as well. Because the exchanged fragments were different sizes, chromosome 9 got longer, and chromosome 22 -which became the Philadelphia chromosome -got shorter.

But scientists didn’t know which genes the swapped segments contained or how they related to cancer. For Heisterkamp and Groffen, the possible connection to ABLr came up when a scientist friend visited them in r982. That friend mentioned that his brother was studying the Philadelphia chromosome at a lab in Rotterdam. Heisterkamp and Groffen soon began collaborating with the Rotterdam group, and the team found that ABLr was located on the Philadelphia chromosome in CML patients. In other words, ABLr had moved from its usual place on chromosome 9 to the now-shortened chromosome 22.

Did ABLr’s movement contribute to the cancer? To answer that question, Heisterkamp and Groffen needed to find out whether ABLr was close to the breakpoint -the seam where the DNA segments from the two chromosomes had been stitched together. If ABLr was near that seam, it was more likely to play an important role in the disease. “Let’s say there’s a burglary, and there’s someone standing right next to your house with a brick in his hand,” says Heisterkamp. The chances that the person was involved in the burglary are higher than if he was found miles away.

To investigate, Heisterkamp and Groffen obtained frozen chunks of spleens that had been removed from CML patients during surgeries. Leukemia cells had accumulated in the patients’ spleens and made the organs swell uncomfortably , so doctors had cut out parts of the enlarged spleens to offer some relief. The researchers sawed off pieces of the spleens using a cast cutter and isolated DNA from the tissue. Then they searched for abnormalities in the ABLr gene in those DNA samples.

Working again with the Rotterdam lab, the scientists discovered that the breakpoint was actually inside ABL1. In other words, only part of the ABLr gene moved to chromosome 22 in CML patients. The beginning of the gene, or the “head,”was left behind on chromosome 9. And when the remaining ABLr fragment, or the “tail,” attached to chromosome 22, it was stitched to another gene named BCR.

As a result, CML patients produced a fused protein. Instead of making a complete ABLr protein, which is what the ABLr gene ordinarily does, their cells produced a mutant protein with a BCR “head” and an ABLr “tail.” Other scientists also found ABLr-related abnormalities in CML patients, adding to the evidence linking this gene to the disease.

Normally, the ABLr protein helps control various processes in the cell by activating other proteins. For instance, these signals can prompt the cell to repair its DNA or kill itself if it’s too severely damaged. But ABLr ‘s “head” keeps ABLr’s activity in check by shutting off the protein when needed. Since the fused BCR-ABLr protein lacked this crucial piece, it stayed active all the time. The problem is similar to a gas leak in your home: If the gas switches off when it’s supposed to, “it’s not a problem,” says Heisterkamp. “But if the gas remains on, you’re going to get an explosion.”Scientists don’t know exactly how the fusion protein causes cancer, but it might activate proteins that the normal ABLr protein wouldn’t activate in normal cells.

Thanks to this work, researchers began to devise drugs to target the fusion protein. Cancer cells become dependent on BCR-ABLr , so if a medication inactivates this protein, the cell dies. The drug imatinib (marketed as Gleevec), approved in the U.S. in 2oor, did exactly that – it killed off cancer cells in chronic phase CML patients with astonishing success. Gleevec can’t eliminate all traces of the cancer, and patients must continue taking the drug for the rest of their lives. But it keeps the disease at bay.

Not all patients respond to Gleevec. Some people have additional mutations in the ABLr gene that allow cancer cells to resist the treatment. But second- and third-generation drugs -called dasatinib, nilotinib, bosutinib, and ponatinib -have largely addressed that problem. Nearly all CML patients can now find a drug that successfully treats their cancer, although they may suffer from side effects. For example, ponatinib can increase the risk of blood clots.

Scientists have found versions of the BCR-ABLr fusion protein in other blood cancers called acute lymphocytic leukemia and acute myeloid leukemia. ABLr also can fuse with other genes besides BCR in those diseases. And the human genome contains a gene very similar to ABLr, called ABL2. ABL2 also activates proteins, and it helps control cell shape and movement. Researchers have discovered that in some leukemias, patients have a fusion protein made of ABL2 and another protein -although again, they don’t know exactly how this chimera contributes to cancer.

The discovery of the Philadelphia chromosome, the BCR-ABLr fusion protein, and Gleevec perhaps represents cancer research’s biggest success. It’s not perfect, though-some patients struggle to afford the drug’s cost or resist the idea of taking medication for the rest of their lives. “It’s hard for people to transition from considering themselves normal and healthy into the realm of the sick,” says Gary Schiller, a hematologist at the David Geffen School of Medicine at the University of California, Los Angeles. “But the majority of the patients accept it with great pleasure because it’s actually one pill with few off-target effects. They’ll have a life.”

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