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Molecular
Genetics and Therapy of Myeloid Leukemia
We have pursued the association between neurofibromatosis 1 (NF1) and
leukemia in human cells and in mice. These studies have shown that NF1
restrains the growth of immature myeloid cells by negatively regulating
Ras signaling. We are exploiting Nf1 mutant mice to investigate how growth
factor signaling contributes to leukemogenesis, and to test targeted therapeutics.
We have also established a model of alkylator-induced leukemia that we
are using to learn how mutagenic compounds cooperate with germline predispositions
to leukemia and to uncover mechanisms of DNA damage in hematopoietic cells.
Chromosome 7 deletions are common in myeloid malignances. We have defined
a commonly-deleted segment of DNA on 7q22 that contains a putative myeloid
tumor suppressor, which we are working to clone. In collaboration with
Nigel Killeen1s lab, we are complementing these human studies by adapting
the chromosome engineering strategy developed by Alan Bradley to generate
segmental deletions of 0.5 - 2 Mb that span genomic segments syntenic
to those that are lost in human leukemias with deletions of 7q22. Mutant
mice and cells from these strains will be used to investigate the effects
on hematopoietic growth and to isolate candidate tumor suppressors.
Selected Publications:
Birnbaum R, O1Marcaigh A, Wardak Z, Zhang Y, Dranoff G, Jacks T, Clapp
DW, Shannon KM. Nf1 and Gmcsf interact in myeloid leukemogenesis. Molecular
Cell 2000; 5: 189-195.
Shannon KM, Le Beau MM, Largaespada DA, Killeen N. Modeling myeloid leukemia
tumor suppressor gene inactivation in the mouse. Semin Cancer Biol 2001;
11: 191-199.
Kratz CP, Emerling BM, Donovan S, Laig-Webster M, Taylor BR, Thompson
P, Jensen S, Banerjee A, Makalowski W, Green ED, Le Beau MM, Shannon KM.
Candidate gene isolation and comparative analysis of a commonly deleted
segment of 7q22 implicated in myeloid malignancies. Genomics 2001, 77:
171-180
Contact Information:
Email: kevins@itsa.ucsf.edu
Phone: 415/ 476-7932
Address: Box 0519, Room HSE 302
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
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