Faculty Bibliography

Mutations are an inherent risk of cell duplication. On one hand, inheritable mutations are the driving force of biological evolution; on the other hand, their accumulation in somatic cells plays a key role in the development of cancer. The frequency of mutants (f) and the rate of mutation (mu) are biological features of any cell population: their measurement could provide important information about the risk of oncogenesis and the exposure to carcinogenic agents. However, the measurement of these parameters is not trivial. To measure f and mu, a potential sentinel gene is the PIG-A gene, which encodes one of the subunits of an enzyme essential in the biosynthesis of glycosylphosphatidylinositol (GPI). Since PIG-A is X-linked, mutational inactivation of the one single copy active in somatic cells entails absence from the cell surface of all the proteins that require GPI for attachment to the membrane: thus, mutant cells display a GPI-negative surface phenotype that can be easily detected by flow cytometry. The measurement of PIG-A mutants by counting cells with the GPI-negative phenotype has proved to be effective to measure mutant frequency in peripheral blood cells of humans and of others animals. Up to now, mu has been exceedingly difficult to measure in human cells; however, by using as a sentinel the PIG-A gene in lymphoblastoid cell lines we now have a test that makes it practical to measure mu in human cells

It has been proposed that hypermutability is necessary to account for the high frequency of mutations in cancer. However, historically, the mutation rate (mu) has been difficult to measure directly, and increased cell turnover or selection could provide an alternative explanation. We recently developed an assay for mu using PIG-A as a sentinel gene and estimated that its average value is 10.6 x 10(-7) mutations per cell division in B-lymphoblastoid cell lines (BLCLs) from normal donors. Here we have measured mu in human malignancies and found that it was elevated in cell lines derived from T cell acute lymphoblastic leukemia, mantle cell lymphoma, follicular lymphoma in transformed phase, and 2 plasma cell neoplasms. In contrast, mu was much lower in a marginal zone lymphoma cell line and 5 other plasma cell neoplasms. The highest mu value that we measured, 3286 x 10(-7), is 2 orders of magnitude above the range we have observed in non-malignant human cells. We conclude that the type of genomic instability detected in this assay is a common but not universal feature of hematologic malignancies

Very few human genes can be used to identify spontaneous inactivating somatic mutations. We hypothesized that because the XK gene is X-linked, it would be easy to identify spontaneously arising red cells with a phenotype resembling the McLeod syndrome, which results from inherited XK mutations. Here, by flow cytometry, we detect such phenotypic variants at a median frequency of 9x10(?6) in neonatal cord blood samples and 39x10(?6) in healthy adults (p=0.004). It may be possible to further investigate the relationship between aging, mutations, and cancer using this approach

ABSTRACT: Pulmonary involvement and skin involvement are rare complications of plasma cell neoplasms. Here we describe what may be the first reported case of a patient with relapse in both of these sites following autologous peripheral blood stem cell transplantation