Several years ago, Caligiuri, together with OSUCCC researchers Clara D. Bloomfield and Carlo M. Croce , discovered this mutation in the MLL gene. The MLL gene stores information for a protein that helps regulate the activity of other genes called Hox (for homeobox) genes, which control many aspects of development.

To make the mouse strain, Caligiuri and his colleagues used genetic engineering techniques to remove a section of the normal MLL gene from one animal and insert it into the MLL gene of another. The result is a strain of mice with a mutation that mimics the one that occurs in human leukemia.

The researchers then looked to see how the mutation affected the animals. The most obvious changes was a missing or rudimentary 13th rib and an additional vertebra in the lower backbone. This suggested the mutation was affecting Hox genes, some of which govern the growth and development of the skeleton and of blood cells.

Next, the researchers examined cells in the bone marrow and spleen that give rise to blood cells. The cells looked normal, as did their numbers. But when the cells were grown in a laboratory test tube, those with the mutation grew far faster and formed much larger colonies than control cells without the mutation.

In addition, cells with the mutation could be used to start new colonies four or more times, while control cells could not. This showed that cells with the mutation lived longer than normal.

Rapid proliferation and unusually long life are features of cancer cells.

Three Hox genes could be involved in the increased proliferation of the progenitor cells. An analysis showed that of the three, the HoxA9 gene was overactive. Its protein was being made at levels much higher
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Contact: Darrell E. Ward
Darrell.Ward@osumc.edu
614-293-3737
Ohio State University
19-Sep-2006