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CSHL team shows how loss of key protein promotes aggressive form of leukemia
Date:7/1/2010

Cold Spring Harbor, NY New research by scientists at Cold Spring Harbor Laboratory (CSHL) has illuminated in fine detail one of the genetic paths that leads to a particularly aggressive form of leukemia.

CSHL Professor Scott W. Lowe. Ph.D., an Investigator of the Howard Hughes Medical Institute, led a team of scientists who wanted to know more about how the absence of an important tumor-suppressing protein called p53 combines with another genetic "hit" in immature blood cells to give rise to acute myeloid leukemia, or AML. In experiments in living mice, the team discovered that if p53 is disabled in immature blood-cell "precursors" in which a mutation in a gene called Kras is also present, a built-in braking mechanism fails to engage and the cells proliferate out of control.

Mutations in p53, the gene that encodes the p53 "master tumor-suppressor" protein, had previously been associated with drug resistance and adverse outcome in AML. The mechanism, however, was a matter of conjecture prior to the new results, which are published in the July 1 issue of Genes & Development.

"Our team has shown how mutations in Kras and p53 act to reinforce one another to change the character of blood precursor cells, transforming them into cells that can renew themselves and thus proliferate indefinitely, somewhat as cancer stem cells are theorized to do," says Lowe.

Under normal conditions, the ability to self-renew is possessed only by stem cells. Once stem cells give birth to "daughter" cells, those cells commit to a developmental pathway, and to a process called differentiation, that ends in their maturation as cells of a specific type. Blood-cell precursors, which are the "daughters" of hematopoietic stem cells, or HSCs, can differentiate into various kinds of mature blood cells, which normally have a finite lifespan. Recently, p53 has been shown to enforce this program in healthy stem cells -- not only HSCs, but also brea
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Contact: Peter Tarr
tarr@cshl.edu
516-367-8455
Cold Spring Harbor Laboratory
Source:Eurekalert

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