Stem-cell researchers solve mystery of relapse in acute myeloid leukemia

June 28, 2017
Dr. John Dick is a Senior Scientist at Princess Margaret Cancer Centre, University Health Network. Credit: University Health Network

Leukemia researchers led by Dr. John Dick have traced the origins of relapse in acute myeloid leukemia (AML) to rare therapy-resistant leukemia stem cells that are already present at diagnosis and before chemotherapy begins.

They have also identified two distinct stem-cell like populations from which relapse can arise in different patients in this aggressive cancer that they previously showed starts in in the bone marrow.

The findings—published today in Nature—provide significant insights into cell types fated to relapse and can help accelerate the quest for new, upfront therapies, says Dr. Dick, a Senior Scientist at Princess Margaret Cancer Centre, University Health Network, and Professor in the Department of Molecular Genetics, University of Toronto. He holds the Canada Research Chair in Stem Cell Biology and is Director of the Cancer Stem Cell Program at the Ontario Institute for Cancer Research. This study was primarily undertaken by post-doctoral fellow Dr. Liran Shlush and Scientific Associate Dr. Amanda Mitchell.

"For the first time, we have married together knowledge of and genetics - areas that historically have often been operating as separate camps - to identify mutations stem carry and how they are related to one another in AML," says Dr. Dick, who pioneered the field by identifying in 1994. A decade ago, he replicated the entire human disease process by introducing oncogenes into normal human blood cells, transplanting them into xenografts (special immune-deficient mice that accept human grafts) and watching leukemia develop - a motherlode discovery that has guided leukemia research ever since.

The researchers set out to solve the mystery of AML relapse by analysing paired patient samples of blood taken at the initial clinic visit and blood taken post-treatment when disease recurred.

"First, we asked what are the similarities and differences between these samples. We carried out detailed genetic studies and used whole genome sequencing to look at every part of the DNA at diagnosis, and every part of the DNA at relapse," says Dr. Dick. "Next, we asked in which cells are genetic changes occurring."

The two-part approach netted a set of mutations seen only at relapse that enabled the team to sift and sort leukemic and normal stem cells using tools developed in the Dick lab a few years ago to zero in on specific cell types fated to relapse.

"This is a story that couldn't have happened five years ago, but with the evolution of deep sequencing, we were able to use the technology at just the right time and harness it with what we've been working on for decades," he says.

Today's findings augment recent research also published in Nature (Dec.7, 2016) detailing the team's development of a "stemness biomarker" - a 17-gene signature derived from leukemia stem cells that can predict at diagnosis which AML patients will respond to standard treatment.

Dr. Dick says: "Our new findings add to that knowledge and we hope that we will soon have a new biomarker that will tell whether a patient will respond to standard chemotherapy, and then another to track patients in remission to identify those where treatment failed and the rare leukemia stem cells are coming back.

"These new kinds of biomarkers will lead to new kinds of clinical trials with targeted chemotherapy. Right now, everybody gets one size fits all because in AML we've never had any opportunity to identify patients upfront, only after they . Now we have the first step to identify these at the outset and during remission."

Explore further: Cancer researchers discover pre-leukemic stem cell at root of AML, relapse

More information: Tracing the origins of relapse in acute myeloid leukaemia to stem cells, Nature (2017). nature.com/articles/doi:10.1038/nature22993

Related Stories

Cancer researchers discover pre-leukemic stem cell at root of AML, relapse

February 12, 2014
Feb. 12, 2014) – Cancer researchers led by stem cell scientist Dr. John Dick have discovered a pre-leukemic stem cell that may be the first step in initiating disease and also the culprit that evades therapy and triggers ...

Stem cell-based test predicts leukemia patients' response to therapy to tailor treatment

December 7, 2016
Leukemia researchers at Princess Margaret Cancer Centre have developed a 17-gene signature derived from leukemia stem cells that can predict at diagnosis if patients with acute myeloid leukemia (AML) will respond to standard ...

Single cell focus reveals hidden cancer cells

May 16, 2017
Researchers have found a way to identify rogue cancer cells which survive treatment after the rest of the tumour is destroyed, by using a new technique that enables them to identify and characterise individual cancer cells.

Clinical importance of leukemia stem cells validated

August 28, 2011
Cancer scientists have long debated whether all cells within a tumour are equal or whether some cancer cells are more potent - a question that has been highly investigated in experimental models in the last decade. Research ...

As leukemia evolves, stem cells hold keys to newer therapies

August 30, 2016
A recent study by University of Rochester Medical Center researchers proves why leukemia is so difficult to treat and suggests that the current approach to drug development should be adjusted to target a broader range of ...

Rare form of leukemia found to originate in stem cells

February 13, 2014
(Medical Xpress)—An international team of researchers working out of the University of Toronto has found that one type of rare leukemia appears to get its start in stem cells. In their paper published in the journal Nature, ...

Recommended for you

No dye: Cancer patients' gray hair darkened on immune drugs

July 21, 2017
Cancer patients' gray hair unexpectedly turned youthfully dark while taking novel drugs, and it has doctors scratching their heads.

Shooting the achilles heel of nervous system cancers

July 20, 2017
Virtually all cancer treatments used today also damage normal cells, causing the toxic side effects associated with cancer treatment. A cooperative research team led by researchers at Dartmouth's Norris Cotton Cancer Center ...

Molecular changes with age in normal breast tissue are linked to cancer-related changes

July 20, 2017
Several known factors are associated with a higher risk of breast cancer including increasing age, being overweight after menopause, alcohol intake, and family history. However, the underlying biologic mechanisms through ...

Immune-cell numbers predict response to combination immunotherapy in melanoma

July 20, 2017
Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco ...

Discovery could lead to better results for patients undergoing radiation

July 19, 2017
More than half of cancer patients undergo radiotherapy, in which high doses of radiation are aimed at diseased tissue to kill cancer cells. But due to a phenomenon known as radiation-induced bystander effect (RIBE), in which ...

Definitive genomic study reveals alterations driving most medulloblastoma brain tumors

July 19, 2017
The most comprehensive analysis yet of medulloblastoma has identified genomic changes responsible for more than 75 percent of the brain tumors, including two new suspected cancer genes that were found exclusively in the least ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.