24 min

A better understanding of acute leukemia

At present, being diagnosed with acute myeloid leukemia (AML) means a grueling course of treatment and a high risk of relapse. Linda Holmfeldt is conducting research to gain a more complete picture of the changes occurring in the cancer cells. The aim is to find new biomarkers for more effective diagnosis and treatment.

Linda Holmfeldt

PhD in Molecular Biology

Wallenberg Academy Fellow 2013

Institution:
Uppsala University

Research field:
Molecular characterization of non-responsive acute leukemia

Linda is starting to settle into her new home town of Uppsala, and at the Rudbeck Laboratory, where she is researching into acute leukemia. She returned to Sweden in spring 2014 after just over four years at St. Jude Children’s Research Hospital in Memphis, Tennessee. Getting the staff and equipment in place has been a big job.

“It is wonderful to set up my own research team, but it takes time. Uppsala has a good research climate for the kind of studies I want to make; here there are key partners for collaboration and contacts at the clinic where leukemia patients are treated.”

“It is an incredible honor to receive this funding. It will be an enormous help in getting going and being able to set up a completely new research team in the field of acute leukemia.”

Whilst in the U.S. she studied how genetic changes lead to acute lymphoblastic leukemia (ALL), the commonest form of cancer in children. Her findings were published in Nature and elsewhere. Her research team at the Rudbeck Laboratory is concentrating mainly on the other form of acute leukemia: AML, which is commonest among adults.

Few make it

In AML the cancer starts in the myeloid cells, a group of white blood cells formed in the bone marrow and serving as part of the body’s immune system.

“AML is diagnosed in about 350 people a year in Sweden. Five-year survival is approximately 15 percent, and many people suffer a relapse. Few survive in the long term,” Linda explains.

Treatment, involving chemotherapy and bone marrow transplants, is very grueling. And it has been roughly the same for forty years.

“We need a better understanding of what has gone wrong in the cells that have become cancerous. We can then use this knowledge to find more effective treatments that are better suited to the individual, and have fewer side effects.”

Linda’s journey from her childhood in a small village near the northern Swedish town of Kalix to the lab in Uppsala has been anything but predictable. She says that chance has played a major part in the course her career has taken. Having graduated in biotechnology at Umeå University, she gained a PhD in molecular biology with a thesis on soil bacteria. Tempted by the opportunity to learn “genomics”, she switched research field and moved to the U.S. to take up a postdoctoral position.

“This method, which studies our DNA in minute detail, has many uses, including studies of all types of leukemia, and also to identify changes that lead to other genetic diseases.”

Battery of tools

In examining how cell changes, including mutations, affect the formation of tumors in AML, Linda is using everything from pure biochemistry and cellular studies (cell lines) to in vivo models, i.e. studies in mice.

Her research team will be comparing blood cells from AML patients who have suffered a relapse with cells from when they had just been diagnosed. This has never been done before at this detailed level. The cell pairs come from biobanks in Uppsala and the Stockholm region, and are kept in the freezer room next to Linda’s office.

“Earlier research has focused on DNA mutations in the initial diagnosis phase. But it is often the relapse that kills the patient; in a relapse the cells formed are almost always resistant to treatment, and we want to understand why.”

Thanks to the new generation of DNA sequencing machines, it is now possible to study the entire DNA of cancer cells at the same time. It is compared with a normal cell sample taken from the same patient. This makes it possible to identify the specific features of a cancer cell.

The team will also be studying “epigenetic” cell changes. These may occur in different parts of the DNA (which contains the genetic code) or of the proteins around which the DNA is coiled.

“Depending on where epigenetic changes occur, and how many of them there are, they may cause a gene to be turned off or switched on, changing the activity in the cell.”

A complete picture

Protein formation in the cells is also being studied. Linda explains that proteins are the cell’s tools; they do the work and initiate activities. In the end the team will have ample data to evaluate.

“The results from the various stages of the cancer cell’s development are of interest individually, but by integrating them and making a systems biology analysis, we hope to gain a complete picture of how the cell works.”

Linda is building her research team from scratch. She acknowledges that the process has been made considerably easier by funding for this purpose from the Knut and Alice Wallenberg Foundation, and the grant from the Wallenberg Academy Fellows.

“Our aim is to find new biomarkers that can be used to simplify diagnosis, predict the course of the disease, and result in new, gentler treatments.”

At St. Jude Children’s Research Hospital there is a cafeteria shared by sick children, their families, medical staff and researchers.

“We were reminded every day why we are doing this research. For that reason I also have a secondary project here at the lab concerning AML in children, and I continue to build on my earlier research findings on ALL in children.”

Text Susanne Rosén
Translation Maxwell Arding
Photo Magnus Bergström

 

Facts

In acute leukemia there is an overproduction of immature white blood cells in the bone marrow, outcompeting production of normal blood cells.

There are two kinds of acute leukemia: myeloid (AML) or lymphoblastic (ALL), depending on the type of blood cell in which the cancer begins.
ALL is most common among children, and AML most common in adults.

At present, leukemia is usually treated with chemotherapy and bone marrow transplants.
Some 350 people are diagnosed with AML in Sweden each year. Almost half of them do not respond to treatment.

Only one in ten patients suffering a relapse is ultimately cured. Of the ten commonest forms of cancer, only lung cancer has a lower survival rate than AML.