Our work aims at curative strategy development for leukemia based on identification and disruption of early genetic lesions that initiate leukemic transformation. While the stem cells in bone marrow are capable of permanent function, most of the cells at risk of genetic mutation are capable only of transient growth before removal from the body. We find that the transient cells can be endowed with permanent growth potential simply by insertion of a gene called HOXB4. Although effectively immortalized, the altered cells continue to produce normal blood cells in normal numbers. However, because their growth potential is unlimited, they are now susceptible to accumulation of gene mutations over time. Our experiments confirm that the immortalized cells do become leukemic after intervals of 18-24 months. Strikingly, early data show that the leukemia that eventually develops can be eliminated by simply removing the HOXB4 gene that was inserted at the beginning of the experiment. The lab is now engaged in researching the mechanisms involved in transforming transient cells into permanent, mutation-accumulating cells, and the mechanisms by which the inserted HOXB4 gene sustains the continued growth of the emerging leukemia. In parallel, we search for operation of the same mechanisms in clinical samples of human leukemia. An understanding of the underlying mechanisms is expected to support the identification of new and potentially curative treatments for human leukemia.
Norman N Iscove, PhD, MD
Emerita/Emeritus Scientist, Princess Margaret Cancer Centre