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Genetically encoded sensor isolates hidden leukaemic stem cells

All stem cells can multiply, proliferate and differentiate.

Because of these qualities, leukaemic stem cells are the most malignant of all leukaemic cells.

Understanding how leukaemic stem cells are regulated has become an important area of cancer research.

A team of Tel Aviv University researchers have now devised a novel biosensor that can isolate and target leukaemic stem cells.

The research team, led by Dr. Michael Milyavsky of the Department of Pathology at TAU's Sackler School of Medicine, discuss their unique genetically encoded sensor and its ability to identify, isolate and characterise leukaemic stem cells in a study published in Leukemia.

"The major reason for the dismal survival rate in blood cancers is the inherent resistance of leukaemic stem cells to therapy," Dr. Milyavsky says. "But only a minor fraction of leukaemic cells have high regenerative potential, and it is this regeneration that results in disease relapse. A lack of tools to specifically isolate leukaemic stem cells has precluded the comprehensive study and specific targeting of these stem cells until now."

Until recently, cancer researchers used markers on the surface of the cell to distinguish leukaemic stem cells from the bulk of cancer cells, with only limited success.

"There are hidden cancer stem cells that express differentiated surface markers despite their stem cell function. This permits those cells to escape targeted therapies," Dr. Milyavsky explains. "By labelling leukaemia cells on the basis of their stem character alone, our sensor manages to overcome surface marker-based issues.

"We believe that our biosensor can provide a prototype for precision oncology efforts to target patient-specific leukaemic stem cells to fight this deadly disease."

The scientists searched genomic databases for "enhancers," the specific regulatory regions of the genome that are particularly active in stem cells.

Then they 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 enhancer is active.

The scientists were also able to demonstrate that sensor-positive leukaemia stem cells are sensitive to a known and inexpensive cancer drug called 4-HPR (fenretinide), providing a novel biomarker for patients who can potentially benefit from this drug.

"Using this sensor, we can perform personalised medicine oriented to drug screens by barcoding a patient's own leukaemia cells to find the best combination of drugs that will be able to target both leukaemia in bulk as well as leukaemia stem cells inside it," Dr. Milyavsky concludes. "We're also interested in developing killer genes that will eradicate specific leukaemia stem cells in which our sensor is active."

The researchers are now investigating those genes that are active in leukaemic stem cells in the hope of finding druggable targets.

Source: American Friends of Tel Aviv University

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European Cancer Organisation European Institute of Oncology

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