Drug resistant leukemia stem cells may be source of genetic chaos, Temple scientists find

December 11, 2012

(Philadelphia, PA) - An international team of scientists, led by researchers from Temple University School of Medicine, has found that a source of mounting genomic chaos, or instability, common to chronic myeloid leukemia (CML) may lie in a pool of leukemia stem cells that are immune to treatment with potent targeted anticancer drugs. They have shown in mice with cancer that even after treatment with the highly effective imatinib (Gleevec), stem cells that become resistant to these drugs - tyrosine kinase inhibitors (TKIs) - may continue to foster DNA damage, potentially leading to disease relapse and a downward spiral to a much more deadly "blast" stage of leukemia.

Identifying a source of such genomic instability may help investigators eventually devise new treatment strategies against drug-resistant CML and other difficult-to-treat diseases.

"We showed that mice that mimic human CML are continuing to accumulate DNA damage - despite treatment with imatinib," said senior investigator Tomasz Skorski, MD, PhD, Professor of Microbiology and Immunology at Temple University School of Medicine. "This implies that whether a patient with CML is being treated or not, DNA damage can continue to accumulate and can confer resistance and possibly lead to relapse in some patients." Dr. Skorski, first author Elisabeth Bolton Gillespie, a graduate PhD student in the Department of Microbiology and Immunology, and their co-workers presented their findings December 11 at the 54th American Society of Hematology Annual Meeting and Exposition in Atlanta.

In CML, an enzyme called ABL1 goes into overdrive because of a chromosomal mix-up that occurs during blood cell development. The genes ABL1 and BCR become fused and produce a hybrid BCR-ABL1 enzyme that is always turned on. This overactive BCR-ABL1 protein drives the excessive production of white blood cells that is the hallmark of CML.

While treatment with imatinib is usually effective in controlling CML growth, it does not eradicate the disease, and small pockets of both active and dormant leukemia stem cells remain. In earlier research, Dr. Skorski and his group showed that both active and quiescent stem cells have more oxidative DNA damage than normal cells.

Tracing Sources of Instability

According to Dr. Skorski, CML in its chronic phase is marked by genomic instability, and results in mutations that cause the cancer to become resistant to TKIs, potentially leading to disease relapse. Understanding the source of such mutations and DNA damage - and instability - could be important in developing new therapies.

"We wanted to understand the mechanism of this genomic instability," Dr. Skorski said. "If stem cells keep accumulating these aberrations, they are like ticking time bombs. Eventually, if they are activated by the accumulation of a right combination of mutations, there is a relapse and/or a blast crisis, which can be fatal. Imatinib keeps the cancer at bay, but if the DNA damage repair process is overwhelmed, resistance occurs, and there may be disease progression."

To determine if TKI-resistant human leukemia stem cells are the source of genomic instability, the researchers turned to a mouse model of chronic phase CML.

"We looked at oxidative DNA damage in stem cells, quiescent stem cells and subpopulations of stem cells and found there is elevated oxidative DNA damage in not only the stem cell pool in CML-like mice but also within a sub-population of leukemia stem cells such as long- and short-term stem cells, and quiescent stem cells," said Ms. Bolton Gillespie.

The researchers subsequently examined the genomic instability within leukemic bone marrow cells, and looked for five common point mutations - alterations in single amino acids - that conferred resistance to imatinib. They also examined the cells for other types of alterations and major changes in genes, such as the loss of copies of genes. They found three of the most common point mutations in mouse cells that conferred drug resistance in animals treated with imatinib as well as in those animals that did not receive the drug.

Link to Leukemia in Patients

"We found numerous genetic aberrations that have already been associated with advanced disease in humans," Ms. Bolton Gillespie said. "We were able to mimic the same kind of oxidative DNA damage and genomic instability in this mouse model that is seen in patients."

"It was very important that we found aberrations in the mice that underwent imatinib therapy," Dr. Skorski said. "The assumption now is that even patients undergoing imatinib treatment will continue to accumulate genetic aberrations. These patients may not be safe. As a result, we feel that patients treated with imatinib may benefit from adding a drug that will stop such genetic aberrations. Ongoing research in our lab is aimed at the development of this approach."
-end-
Other investigators contributing to this work include: Margaret Nieborowska-Skorska, Sylwia Flis, Temple University School of Medicine; Mirle Schemionek, Steffen Koschmieder, University Hospital of Aachen, Aachen, Germany; Hans-Urlich Klein, Linda Kerstiens, University of Munster, Munster, Germany; Grazyna Hoser, Medical Center for Postgraduate Education, Warsaw; Thoralf Lange, University of Leipzig, Leipzig, Germany; Martin C. Muller, Universitat Heidelberg, Mannheim; and Hardik Modi and Ravi Bhatia, City of Hope National Medical Center, Duarte, CA.

The research was supported by funding from the National Institutes of Health grants R01CA123014 and R01CA134458.

About Temple Health

Temple Health refers to the health, education and research activities carried out by the affiliates of Temple University Health System and by Temple University School of Medicine.

Temple University Health System (TUHS) is a $1.4 billion academic health system dedicated to providing access to quality patient care and supporting excellence in medical education and research. The Health System consists of Temple University Hospital (TUH), ranked among the "Best Hospitals" in the region by U.S. News & World Report; TUH-Episcopal Campus; TUH-Northeastern Campus; Fox Chase Cancer Center, an NCI-designated comprehensive cancer center; Jeanes Hospital, a community-based hospital offering medical, surgical and emergency services; Temple Transport Team, a ground and air-ambulance company; and Temple Physicians, Inc., a network of community-based specialty and primary-care physician practices. TUHS is affiliated with Temple University School of Medicine.Temple University School of Medicine (TUSM), established in 1901, is one of the nation's leading medical schools. Each year, the School of Medicine educates approximately 720 medical students and 140 graduate students. Based on its level of funding from the National Institutes of Health, Temple University School of Medicine is the second-highest ranked medical school in Philadelphia and the third-highest in the Commonwealth of Pennsylvania. According to U.S. News & World Report, TUSM is among the top 10 most applied-to medical schools in the nation.

Temple University Health System

Related Stem Cells Articles from Brightsurf:

SUTD researchers create heart cells from stem cells using 3D printing
SUTD researchers 3D printed a micro-scaled physical device to demonstrate a new level of control in the directed differentiation of stem cells, enhancing the production of cardiomyocytes.

More selective elimination of leukemia stem cells and blood stem cells
Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia.

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.

First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.

Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.

New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.

NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.

Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.

Read More: Stem Cells News and Stem Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.