Scientists Induce A Form Of Leukemia In Mice, Gaining An Unprecedented Glimpse Into The Disorder's Roots

November 13, 1998

WALTHAM, Mass. -- In a finding that promises to expand greatly the scope of leukemia research, scientists at Brandeis University have induced a form of the disease in mice that's strikingly similar to chronic myelogenous leukemia (CML), which affects humans. The development gives researchers their best opportunity yet to probe CML's molecular origins, tracing it from a simple mutation involving two genes into a disease that accounts for fully one-fifth of all leukemia patients.

Ruibao Ren, assistant professor of biology in Brandeis' Rosenstiel Basic Medical Sciences Research Center, and Xiaowu Zhang, a graduate student in biochemistry, have accomplished what a host of leukemia researchers have been striving toward for years: essentially using gene therapy in reverse, they incorporated a leukemia-inducing gene into a mouse's genome with the help of a retrovirus. The work, sponsored by the National Cancer Institute and the American Cancer Society, appears in the Nov. 15 issue of the journal "Blood"; a second group from the University of Pennsylvania reports similar findings in the same issue.

Scientists understand the basics of how CML arises: in a single marrow cell, the genes bcr and abl, usually found on separate chromosomes, brush up against each other and fuse into a new gene called bcr-abl. This entity is a known oncogene, a genetic precursor to cancer. How the disease mushrooms from this isolated genetic flaw in just one of the body's trillion cells into a widespread cancer of the body's white blood cells remains a mystery, though.

"Owing to their medical importance, CML's molecular mechanisms have long been the subject of intense study," Ren says. "But there's a lot we have yet to learn about the pathways by which it and other leukemias arise."

For a decade, scientists' primary avenues of CML research have been the study of tumor cells removed from CML patients and the study of inserted oncogenes' effects on animal cells growing in petri dishes. However, these approaches can't do justice to the complexity of a disease that eventually affects blood cells throughout the body. With the development of the first effective and efficient animal models of CML, Ren's group has succeeded in laying the genetic bedrock for the disease -- meaning they can now observe the disorder's progress from its earliest stages, looking for the weak link in the process that might be vulnerable to drugs.

A number of other scientists have taken approaches more similar to Ren's over the last decade, splicing leukemia genes into the mouse genome. But these previous attempts worked very slowly when they worked at all; often months or even years elapsed between the insertion of a gene and the development of leukemia in a mouse, hobbling research projects. For as-yet unknown reasons, Ren's tactic works much more efficiently and predictably.

After preliminary work with the mouse model, Ren suspects the bcr-abl oncogene may induce leukemia by spurring production of growth factors that cancerous cells need in order to survive. He's now examining whether strains of mice that are genetically incapable of producing these growth factors remain healthy even in the presence of an inserted bcr-abl oncogene.

"Since cancerous cells need certain growth factors, it's possible that targeting them may hold the key to controlling CML," Ren says. "We probably won't be able to prevent the disease from arising, but we may be able to use these growth factors to nip it in the bud."

The only treatments now available for leukemia are bone marrow transplants and chemotherapy, neither of which are viable options for many sicker patients. Through their studies with mice, Ren and his colleagues hope to identify potential new leukemia therapies.

Brandeis University

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