Research suggests that patients with leukemia sometimes relapse because standard chemotherapy fails to kill the self-renewing leukemia initiating cells, often referred to as cancer stem cells. In such cancers, the cells lie dormant for a time, only to later begin cloning, resulting in a return and metastasis of the disease.
One such type of cancer is called pediatric T cell acute lymphoblastic leukemia, or T-ALL, often found in children, who have few treatment options beyond chemotherapy.
A team of researchers – led by Catriona H. M. Jamieson, MD, PhD, associate professor of medicine at the University of California, San Diego School of Medicine and Director of Stem Cell Research at UC San Diego Moores Cancer Center – studied these cells in mouse models that had been transplanted with human leukemia cells. They discovered that the leukemia initiating cells which clone, or replicate, themselves most robustly activate the NOTCH1 pathway, usually in the context of a mutation.
Earlier studies showed that as many as half of patients with T-ALL have mutations in the NOTCH1 pathway – an evolutionarily conserved developmental pathway used during differentiation of many cell and tissue types. The new study shows that when NOTCH1 activation was inhibited in animal models using a monoclonal antibody, the leukemia initiating cells did not survive. In addition, the antibody treatment significantly reduced a subset of these cancer stem cells (identified by the presence of specific markers, CD2 and CD7, on the cell surface.)
“We were able to substantially reduce the potential of these cancer stem cells to self-renew,” said Jamieson. “So we’re not just getting rid of cancerous cells: we’re getting to the root of their resistance to treatment – leukemic stem cells that lie dormant.”
The study results suggest that such therapy would also be effective in other types of cancer stem cells, such as those that cause breast cancer, that also rely on NOTCH1 for self-renewal.
“Therapies based on monoclonal antibodies that inhibit NOTCH 1 are much more selective than using gamma-secretase inhibitors, which also block other essential cellular functions in addition to the NOTCH1 signaling pathway,” said contributor A. Thomas Look, MD of Dana-Farber/Children Hospital Cancer Center in Boston. “We are excited about the promise of NOTCH1-specific antibodies to counter resistance to therapy in T-ALL and possibly additional types of cancer.”
In investigating the role of NOTCH1 activation in cancer cell cloning, the researchers showed that leukemia initiating cells possess enhanced survival and self-renewal potential in specific blood-cell, or hematopoietic, niches: the microenvironment of the body in which the cells live and self-renew.
The scientists studied the molecular characterization of CD34+ cells – a protein that shows expression in early hematopoietic cells and that facilitates cell migration – from a dozen T-ALL patient samples.
They found that mutations in NOTCH1 and other genes capable of promoting the survival of cancer stem cells co-existed in the CD34+ niche. Mice transplanted with CD34-enriched NOTCH1 mutated T-ALL cells demonstrated significantly greater leukemic cloning potential than did mice without the NOTCH1 mutation. The mutated cells were uniquely susceptible to targeted inhibition with a human monoclonal antibody, according to the scientists.
Additional contributors to the study include Wenxue Ma, Daniel J. Goff, Ifat Geron, Anil Sadarangani, Christina A. M. Jamieson, Angela C. Court, Alice Y. Shih, Qingfei Jiang, Christina C. Wu, Kristen M. Smith, Leslie A. Crews, Ida Deichaite, Sheldon R. Morris and Dennis A. Carson, UC San Diego Department of Medicine and Stem Cell Program, UC San Diego Moores Cancer Center; Alejandro Gutierrez, Dana-Farber/Children Hospital Cancer Center in Boston; and Kang Li, Ping Wei and Neil W. Gibson, Oncology Research Unit, Pfizer Global Research and Development, La Jolla Laboratories, San Diego.
This work was supported by the Ratner Family Foundation, the Leichtag Family Foundation, and Moores Cancer Center Donor Funds; grants from the National Institute of Health (1K08CA133103 and 5P01CA68484); the William Lawrence Foundation, and the American Society of Hematology-Amos Medical Faculty Development program. Jamieson’s work was supported by the California Institute for Regenerative Medicine (CIRM).
Debra Kain | Newswise Science News
Single-stranded DNA and RNA origami go live
15.12.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard
New antbird species discovered in Peru by LSU ornithologists
15.12.2017 | Louisiana State University
DNA molecules that follow specific instructions could offer more precise molecular control of synthetic chemical systems, a discovery that opens the door for engineers to create molecular machines with new and complex behaviors.
Researchers have created chemical amplifiers and a chemical oscillator using a systematic method that has the potential to embed sophisticated circuit...
MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.
Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...
Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...
Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.
To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...
The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.
Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...
11.12.2017 | Event News
08.12.2017 | Event News
07.12.2017 | Event News
15.12.2017 | Power and Electrical Engineering
15.12.2017 | Materials Sciences
15.12.2017 | Life Sciences