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MERIT Award Recipient: Kevin Shannon, M.D.

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Sponsoring NCI Division: Division of Cancer Biology (DCB)
Grant Number: R37 CA072614-11
Award Approved: September 2006
Institution: University of California at San Francisco, CA
Department: Pediatrics
The Shannon Lab
Literature Search in PubMed

Translation Investigation of KRas & NF1 in Myeloid Leukemia

Studies of individuals who are at increased risk of developing leukemia and other cancers because of an inherited condition can uncover genes and proteins that are crucial for controlling the growth of normal cells and tissues, and are disrupted in cancer. Children with neurofibromatosis, type 1 (NF1), a common genetic disorder, show an elevated rate of juvenile myelomonocytic leukemia (JMML) and other specific cancers. JMML is an aggressive type of leukemia characterized by excessive numbers of malignant blood forming cells that invade into the spleen, liver, skin, and other organs.

Dr. Shannon's research has shown showed that the NF1 gene normally restrains the growth of immature blood forming cells of the myeloid lineage. The NF1 gene performs this function by coding for a protein that inhibits the Ras signaling pathway in cells. In many JMML patients, both copies of the NF1 gene are mutated. This results an over-active Ras protein that leads to in uncontrolled growth of immature myeloid cells. Dr. Shannon's laboratory has used a strain of mice with a mutation in the mouse NF1 gene (this gene is called Nf1) to learn more about how abnormal Ras activity contributes to human leukemia and to test the therapeutic effects of molecularly targeted drugs that might inhibit over-active Ras. Most human cancers are thought to carry mutations in a number of different genes, and Dr. Shannon's is working to discover new genes that cooperate with over-active Ras in cancer development and progression.

Many persons with the genetic disorder Noonan syndrome (NS) inherit a mutation in the PTPN11 gene, which encodes a protein called SHP-2 that also regulates Ras activity. Reports of JMML in some children with NS suggested that PTPN11 mutations might occur in leukemia. Indeed, acquired PTPN11 mutations are found in 35% of JMML samples from children without NS. These mutant genes produce SHP-2 proteins with abnormal biochemical properties that cause Ras to become over-active. Recently, a child with NS who developed JMML unexpectedly revealed inherited KRAS gene mutations as another cause of NS. These mutations, which introduce different amino acid substitutions from the acquired KRAS alterations found in many human cancers, encode proteins with novel biochemical and functional properties. Dr. Shannon's studies of JMML samples from children with NF1 and NS and data from Nf1 mutant mice are consistent with the idea that mutations that cause abnormal Ras signaling could be the first step in myeloid leukemia. Recent studies from his lab demonstrating that turning on a latent Kras oncogene in mouse bone marrow cells causes a fatal myeloid disease that resembles JMML strongly support this idea. These mice provide a robust model for investigating the biochemical and cellular consequences of expressing the Kras oncogene in normal cells.

Dr. Shannon is exploiting the ability to inactivate Nf1 or to turn on Kras oncogene expression at specific times in mouse bone marrow cells to understand how these mutations alter gene expression and biochemical networks in individual cells. Strains of Nf1 and Kras mutant mice also provide excellent systems for identifying new cancer genes and for determining how these secondary mutations influence treatment responses. The ongoing research supported by this MERIT award is addressing these general questions in cancer biology and therapeutics.