Researchers in Tel Aviv have devised a novel biosensor that can isolate and target leukemic stem cells. The team, led by Michael Milyavsky, MD, of the department of pathology at Tel Aviv University’s Sackler School of Medicine, described the sensor in a study reported in Leukemia.
The ability of stem cells to multiply, proliferate, and differentiate results in leukemic stem cells being the most malignant of all leukemic cells. Much of recent cancer research has focused on understanding the regulation of leukemic cells.
“The major reason for the dismal survival rate in blood cancers is the inherent resistance of leukemic stem cells to therapy,” Dr. Milyavsky said. “But only a minor fraction of leukemic cells have high regenerative potential, and it is this regeneration that results in disease relapse. A lack of tools to specifically isolate leukemic stem cells has precluded the comprehensive study and specific targeting of these stem cells until now.”
Targeting “Hidden” Cancer Stem Cells
The present study was designed to test the hypothesis that tagging endogenous stemness-regulatory regions could generate a genome reporter for the putative leukemia stemness-state. Prior to the study, cancer researchers used markers on the surface of the cell to distinguish leukemic stem cells from the bulk of cancer cells, a technique that resulted in only limited success.
“There are hidden cancer stem cells that express differentiated surface markers despite their stem cell function,” Dr. Milyavsky said. “This permits those cells to escape targeted therapies. By labeling leukemia cells on the basis of their stem character alone, our sensor manages to overcome surface marker-based issues.”
The researchers searched genomic databases for enhancers, the specific regulatory regions of the genome that are particularly active in stem cells. They then harnessed genome engineering to develop a sensor composed of a stem cell active enhancer fused with a fluorescence gene that labels the cells in which the enhanced is active. The analysis revealed that the ERG + 85 enhancer region can serve as a marker for stemness-state and a fluorescent lentiviral reporter was developed that can accurately recapitulate the endogenous activity. The researchers also reported that RNA-sequencing analysis coupled with in silico drug-screening analysis singled out 4HPR as an effective inhibitor of ERG + 85high leukemia growth.
“Using this sensor, we can perform personalized medicine oriented to drug screens by barcoding a patient’s own leukemia cells to find the best combination of drugs that will be able to target both leukemia in bulk as well as leukemia stem cells inside it,” Dr. Milyavsky said.
“We’re also interested in developing killer genes that will eradicate specific leukemia stem cells in which our sensor is active,” he added.