Fall 2004

Searching for the Genetics of Leukemia

Dr. Kevin Shannon, a pediatric cancer specialist, and his colleagues receive blood and bone marrow samples from doctors and parents all over the world who want to know if he can tell them why their child or patient has leukemia. For 18 years, Shannon has been searching for the pieces of genetic machinery that go awry and give rise to myeloid leukemia. Every sample he receives offers the possibility of finding something new.

"The general idea is to learn from our patients about the disease they have and to dig down into the genetic abnormalities and learn from them," Shannon says. "Although children who develop leukemia in the context of another genetic condition are rare, studying those leukemia cells can uncover critical proteins and biochemical pathways that control the growth of immature blood cells. The ultimate goal is to use this information to develop smarter drugs that can target these molecular defects."

In most cases, unfortunately, Shannon cannot tell parents why their kids have cancer, but the continuing search has yielded some major discoveries that may point to common pathways that cause the development of all leukemias.

"Over the last 18 years, we've hit some home runs," Shannon says. The risk of getting leukemia, he points out, is much higher in children who previously received chemotherapy or radiation to treat another cancer, children who have Down's syndrome or those who have neurofibromatosis (NF1). "Children with NF1 have café au lait spots and are also predisposed to getting brain tumors and benign skin tumors," he says.

Shannon and his colleagues have discovered that the NF gene is deleted in some kids with leukemia. The NF gene is known to turn off the protein produced by the Ras proto-oncogene, which normally relays signals between cell surface receptors and cell machinery responsible for growth. These studies tend to implicate a hyperactive Ras gene as a critical player in the growth of leukemia cells, Shannon says. This idea is consistent with work from many labs around the world showing that the Ras gene is itself mutated in many cancers.

Dr. Mignon Loh, a cancer specialist, works closely with Shannon on studies of another gene called PTPN11. Mutations in PTPN11 cause a genetic disease called Noonan syndrome, which is occasionally associated with myeloid leukemia. It happens that the PTPN11 gene produces a protein linked to the Ras pathway, which suggested that this gene might be mutated in leukemia. Indeed, the UCSF researchers, and a group led by Dr. Bruce Gelb at the Mount Sinai School of Medicine in New York, independently discovered new PTPN11 gene mutations in leukemia cells from children who do not have Noonan syndrome. Shannon notes that these studies are an important piece of evidence that Ras can be an important actor in the initiation of leukemia.

"Based on our studies in children and in strains of mutant mice, we would argue that the Ras pathway is aberrantly activated in all myeloid leukemias," Shannon says. "The field has now come around to the view that at least in the vast majority of cases this is true."

While this establishes hyperactive Ras as a major target for developing "smart" new cancer drugs, Shannon warns that it will be difficult to selectively inhibit "bad" Ras signals in cancer cells without impairing "good" Ras signals that are crucial for the growth of normal cells.

Other research paths have been much more daunting. When Shannon first started this work in 1986, he decided to find the gene on chromosome 7 that contributes to leukemia. This work again began with studies of familial cases, but has broader implications. Chromosome 7 deletions are found in about 10 percent of all myeloid leukemias, and these cases are particularly deadly. After 18 years of hunting for the gene, the search still continues, Shannon says.

One of Shannon's goals is to build better research tools. He has been doing this by taking the mutations found in human leukemias and engineering them into mouse bone marrow cells. "We have built a number of mouse leukemia models that we and others are using," Shannon says. The ultimate goal is to be able to find chemical agents that can target the wayward proteins. "If you can find the mutation and turn that protein off, it would be a better way to treat leukemia than chemotherapy or radiation," Shannon says.

As part of the effort to turn research insights into clinical accomplishments, Shannon, Loh and their colleagues are involved in national trials for new therapeutic compounds. The UCSF research team is assessing samples from children with juvenile myelomonocytic leukemia (JMML) who are being treated in a national clinical trial with new compounds that inhibit Ras in leukemia, Shannon says.

Shannon can be contacted at (415) 476-7932.

Loh can be contacted at (415) 514-0853.

Pediatric Cancer and Blood Diseases (415) 476-3831

UCSF Benioff Children's Hospital offers diagnosis and therapy for all malignant diseases in children. Bone marrow transplants with matched, mismatched and unrelated donors are performed for a variety of hematologic and solid malignancies. We also provide the only pediatric brain tumor treatment program in California funded by the National Institutes of Health (NIH). Access to national clinical trails and investigational treatments is available through our Sickle Cell Center, funded by the NIH, our regional Hemophilia Treatment Center and the Children's Oncology Group.

 

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