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New method developed to expand blood stem cells for bone marrow transplant
Date:3/21/2013

es are thus far the most efficient means to deliver therapeutic genes into HSCs in the laboratory setting. In the past, scientists used a virus as a vehicle to deliver a therapeutic gene into patients with severe combined immunodeficiency disease (SCID) to correct their immune deficiency. However, four children receiving SCID gene therapy developed treatment-related leukemia due to the inability to control where the virus inserts itself in the genome, often on the so-called "hot spots" that activate oncogenes or inactivate tumor suppressor genes. Also, other investigators have shown that it is possible to directly insert HOXB4 protein into extracted bone marrow stem cells. "All you do is add a little tag to the protein, which acts like a vehicle, driving the proteins through the cell membrane, directly into the nucleus," Dr. Zhou says. "But the half-life of the natural protein is very short -- about one hour. So that means that in order to expand blood stem cells, these HOXB4 proteins have to be added all the time. Because the proteins are very costly, this process is both expensive and impractical."

Dr. Zhou and his team, in collaboration with Dr. Malcolm A. S. Moore's group from Memorial Sloan-Kettering Cancer Center, took a different approach. They examined why HOXB4 protein doesn't last long in HSCs, once these cells are removed from the protective stem cell niche that they nest quietly in. They found that HOXB4 is targeted for degradation so that stem cells can start differentiating -- that is, turn into different kinds of adult blood cells. "HOXB4 prevents blood stem cells from differentiating, while, at the same time, allows them to renew themselves," Dr. Zhou says.

The researchers found that a protein, CUL4, is tasked with recognizing HOXB4 and tagging it for destruction by the cell's protein destruction apparatus. They discovered that CUL4 recognizes HOXB4 because it "sees" a set of four amino acids on the protein. "HOXB4 carries a destru
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Contact: Lauren Woods
Law2014@med.cornell.edu
646-317-7401
Weill Cornell Medical College
Source:Eurekalert

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