Inhibiting NOTCH1 kills LSCs in T-ALL

Leukemia stem cells
Credit: Robert Paulson

NOTCH1 signaling promotes leukemia stem cell (LSC) regeneration in T-cell acute lymphoblastic leukemia (T-ALL), according to a study published in PLoS ONE.

The researchers studied LSCs in mouse models of T-ALL and found that, when NOTCH1 activation was inhibited using a monoclonal antibody, LSCs did not survive.
 
“We were able to substantially reduce the potential of these cancer stem cells to self-renew,” said study author Catriona H. M. Jamieson, MD, PhD, of the University of California, San Diego.

“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.”

In investigating the role of NOTCH1 activation in cancer cell cloning, the researchers showed that LSCs possess enhanced survival and self-renewal potential in specific hematopoietic niches.

The team studied the molecular characterization of CD34+ cells 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 mice without the NOTCH1 mutation. And the mutated cells were uniquely susceptible to targeted inhibition with a human monoclonal antibody.

These results suggest that such therapy would also be effective in other types of cancer stem cells that rely on NOTCH1 for self-renewal, the researchers said.

“Therapies based on monoclonal antibodies that inhibit NOTCH1 are much more selective than using gamma-secretase inhibitors, which also block other essential cellular functions in addition to the NOTCH1 signaling pathway,” said study author A. Thomas Look, MD, of the Dana-Farber Cancer Institute 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.”

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