Associate Professor in Residence, Emeritus, Pediatrics
School of Medicine

Methylthioadenosine phosphorylase deficiency

Dr. Chilcote's laboratory is studying methylthioadenosine phosphorylase deficiency and its relationship to a possible gene on chromosome 9p in leukemia. Dr. Chilcote hypothesizes that chromosomal changes taking place at the time of malignant transformation have a direct relationship to the response of the cancer to chemotherapy. In some instances, inactivation of homozygous regions of a chromosome may not only impair the function of so-called 'suppressor genes', but the same changes may also inactivate nearby enzymes, giving the malignant clone an occult metabolic vulnerability. This hypothesis is analogous to the retinoblastoma model, where the putative Rb suppressor gene is inactivated at 13q along with homozygotization of the nearby gene, esterase D. In the retinoblastoma model, if a metobolic handicap is produced by the alteration of esterase D, it is of no apparent consequence to the phenotype of retinoblastoma. By contrast, in some patients with leukemia, Dr. Chilcote hypothesizes the loss of methylthioadenosine phosphorylase (MeSAdo-P) activity, an enzyme important to purine salvage in the manufacture of new DNA for cell division, may make these cells susceptible to inhibitors of de novo purine synthesis such as methotrexate. Cells from several additional patients with acute lymphoblastic lymphoma (ALL), as well as a variety of cell lines derived from ALL patients, showed complete loss of MeSAdo-P activity. Significant progress has been made in localizing the gene for MeSAdo-P to chromosome 9p21, in a region where it is tightly linked to loss of the alpha and beta1 interferon genes. MeSAdo-P-deficient cell lines are more susceptible in an in vivo mouse model to the de novo purine synthesis inhibitor methotrexate, than are MeSAdo-P-positive lines. Study of a MeSAdo-P deficient cell lines may be helpful in identifying a tumor suppressor gene, and also for cloning of the gene for MeSAdo-P. Recently, MeSAdo-P deficiency was also detected in a portion of other human tumor cell lines such as breast cancer. A patient's congenital loss of the short arm of chromosome 9p has been identified and that patient has developed acute lymphoblastic leukemia, supporting the role of chromosome 9p as a site of a suppressor gene.

Link to this profile
https://faculty.uci.edu/profile/?facultyId=2952

Last updated
04/17/2002