The Story of FLT3

GENE STORY

The Story of FLT3

The story of FLT3 is also the story of Lukas Wartman, doctor and patient: his diagnosis and treatment led researchers to a deeper understanding of some leukemias.

FLT3 Mutations at a Glance
  • FLT3 mutations are frequent in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), and testing for an FLT3 mutation in AML patients is now standard care. These mutations have also been seen with less frequency in melanoma and lung cancer.

  • In healthy tissue, FLT3 helps the blood and immune systems divide and form appropriately. When mutated, this machinery goes awry, leading to uncontrolled formation of blood cells.

  • Testing positive for an FLT3 mutation can impact treatment. Drugs such as sunitinib (marketed as Sutent) can block the activity of the proteins FLT3 encodes.

  • Clinical trials for FLT3 as a prognostic marker, and on other treatments that inhibit FLT3, are ongoing.

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FLT3

This gene is also known as:

FLT3, CD135, FLK-2, STK1, FLK2, FLT-3, STK-1

Lukas Wartman began his medical career at Washington University in St. Louis in 1999 as a medical student with a goal: he wanted to study cancer and treat cancer patients. He would never have guessed, at the time, that he would be diagnosed with the very cancer he was studying.

In his last year of medical school, at age 25, Lukas was diagnosed with acute lymphoblastic leukemia (ALL). The name of that disease alone is a mouthful: it describes a condition where the bone marrow is making immune cells that are more immature than mature.

After his diagnosis, Lukas underwent two years of chemotherapy, which gave him enough time to complete clinical training. Yet, in 2008, Lukas’s cancer came back—and with a vengeance. This time, he was treated with high-dose chemotherapy and a stem-cell transplant from his younger brother. This combination treatment offered Lukas a reprieve and put him back in remission for a second time.

Although few adults (4 to 5 percent) diagnosed with ALL survive one relapse, there are almost no statistics on surviving a second relapse. So when Lukas relapsed a second time in 2011, he knew time was running short.

In July 2011, Dr. Timothy Ley, Lukas’s mentor, had the idea to sequence his genome. That way, perhaps, they could find a genetic reason for why his leukemia was so aggressive. Dr. Ley studies the genetics of leukemias similar to the one Lukas had. His lab was the first to publish the whole cancer genome of a patient who had acute myeloid leukemia (AML) and was using sequencing approaches to understand the genetics of similar cancers.

To understand what was going on within Lukas’s tumor, Dr. Ley took both healthy and cancerous blood cells from him and compared their profiles. What was going awry, specifically in the tumor cells? From both cell types, he sequenced and compared both the DNA—the genomic blueprint of our cells—and RNA, a closely related cousin of DNA that tells us which genes are actually being turned on.

One of those gene culprits was FLT3.

Like many other genes in our body, the FLT3 gene encodes for a protein with a rather convoluted name: FMS-like tyrosine kinase 3 (or just the FLT3 protein).

During the time between when you were conceived to the day of your birth, FLT3 played a pivotal role to ensure blood could course through your veins and that your immune system would be set up with the correct troops in the right ratios to properly fight infection. FLT3 is almost exclusively found on the immature blood cells that call the bone marrow home. These cells have the ability to differentiate into the distinct, mature components of a person’s immune system.

In the cell, FLT3 is found in the plasma membrane—a barrier that separates the cell’s innards from the external environment. Proteins like FLT3 span the length of the membrane and poke out on both sides to relay messages they sense from outside the cell and transmit them inside.

If we imagine the structure of FLT3 to resemble an old-school telephone, we would see its receiving end outside the cell and the neck traversing through the membrane to relay messages at the speaker end, which is located on the inside of the cell. Messages to FLT3 are often relayed from the outside to the inside of its cell when the protein binds with its partner, called the FLT ligand.

When the FLT ligand binds to its receptor, the speaker end relays the message to the nucleus to turn on the proper genes to divide and proliferate. Activation of FLT3 during normal developmental processes ultimately leads to the formation of the blood and immune systems. Under normal circumstances, if the FLT ligand does not bind with FLT3, the differentiation and growth pathways associated with FLT3 do not budge, either.

However, FLT3 behaves differently in the context of cancer. In tumors, mutations occur in the gene sequence of FLT3. These mutations change the speaker end of the FLT3 protein and leave the protein in an activated state such that the cells constantly divide. This relatively uncontrolled division causes improper formation of blood cells and can lead to the formation of blood cancers like AML and ALL.

Given FLT3’s normal role in forming the blood system, it is unsurprising that mutation of FLT3 leads to the formation of blood cancers. Mutations that lead to elevated FLT3 activity are now recognized as the most common molecular marker in AML. Over 30 percent of AML patients have activating mutations within the tyrosine kinase domain (the receiving end of the protein). FLT3 is also found in excess in AML patients. A situation where there is an overabundance of overactive FLT3 is analogous to having a nursery full of fussy, overactive toddlers: it ultimately becomes too much of a burden for the surrounding system to bear. (FLT3 mutations have also been seen in solid tumors like melanoma and lung cancer, although they are much less frequent than in leukemia.)

Testing for mutations in FLT3 is now considered the standard of care for patients diagnosed with AML. Drugs can be administered to halt the activity of FLT3 and other similar receptor tyrosine kinases. These drugs, referred to as tyrosine kinase inhibitors, enter the cell membrane and bind to the speaker end of the protein, halting any signals the protein could be sending to the nucleus to divide or differentiate. FLT3 mutation status can be indicative of the risk for relapse, although it does not necessarily mean that mutations result in a poor cure rate.

Happily for Lukas, after identifying FLT3 as a gene that was potentially causing his cancer, his doctors started him on sunitinib (marketed under the name Sutent), a drug manufactured by Pfizer and originally approved to treat advanced kidney cancer. Sutent can block tyrosine kinase activity, like that of FLT3.

After he began treatment with Sutent, Lukas’s blood counts quickly returned to normal. At first, he thought it was a fluke, but additional tests confirmed that his cancer was indeed cleared. Today, Lukas still receives bone marrow transplants and is back to the bench in Dr. Ley’s lab.

While he is still left with the uncertainty of if and when his cancer will come back, he gets the opportunity to help us learn more about ourselves.

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