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NFRP 2012 Investigator Vignette

Title: Preclinical Mouse Models of Neurofibromatosis

Investigator: Kevin Shannon, MD; University of California, San Francisco

People with neurofibromatosis are predisposed to certain kinds of childhood types of leukemia. When I started my research in this area, I was interested in a disease called juvenile myelomonocytic leukemia, or JMML. This is a very aggressive myeloproliferative disorder, and it has a very poor prognosis in contrast to many childhood leukemias. It affects only young children, and most kids with JMML do not respond at all to conventional therapies, and the only known cure is bone marrow transplantation, which is a pretty difficult procedure for a young child.

And unraveling the puzzle of why children with NF1 develop JMML led us to do experiments where we collected bone marrow specimens from children with JMML and blood samples from their parents. And we would just analyze them genetically at the level of the NF1 gene. And you can see this mother has neurofibromatosis. This is one copy of her NF1 gene. This is the other copy. Her husband, who doesn't have neurofibromatosis, you can see this band is darker because both copies of his NF1 gene are migrating at this 399 base-pair position.

You can see their son has inherited in his normal tissues a copy from his father. And since both mother and son have neurofibromatosis, this is the copy of the gene with the mutation in it. When he developed juvenile myelomonocytic leukemia, and we sampled his JMML cells at different time points, you can see that every time we no longer see the copy that he inherited from his father; that this copy, this normal copy of the gene that is helping to control the growth of these bone marrow cells, has been lost, and he only has a mutated copy of the NF1 gene that he inherited from his mother in these leukemia cells. And this work was funded, actually, by the first real research grant I received when I was a faculty member when I came to UCSF 20 years ago from the DoD.

And so, what we've done in our laboratory, is taken mice with a mutation in the NF1 gene, and then used viruses to create new mutations in very aggressive transplantable leukemias that we can passage into recipient mice and use for drug trials. And our current DoD grant is to now use this leukemia model as sort of a first proof-of-principle of combining targeted and non-targeted inhibitors to treat a very aggressive form of NF associated cancer. And we think this will be a model not only for NF-associated cancers, but for other cancers that are going to require treatments with multiple different kinds of agents, both common chemotherapy agents and targeted agents.

My own guess is that we're going to have to be combining all of these modalities to really make a big dent in a lot of these very aggressive cancers that have given us so much, you know, heartache and trouble up until now.

Note: Dr. Shannon's preclinical mouse models spans awards in 1996, 1999, 2001, 2004 and 2011.