Genetic Analysis of Growth Control 
velopment of meningiomas, a specific class of 
brain tumors that originate in the thin membrane 
covering the brain and spinal cord. Meningiomas 
are one of the most common tumors of the central 
nervous system, accounting for up to 20 percent 
of all intracranial tumors and 25 percent of intra- 
spinal neoplastic lesions. Currently the mecha- 
nisms responsible for the initiation and progres- 
sion of these tumors are largely unknown. 
Extensive cytogenetic analyses, coupled with 
recent DNA studies, suggest that meningiomas re- 
sult from the loss of function of a tumor suppres- 
sor gene, the meningioma susceptibility locus 
(msl), located on human chromosome 22. It is 
proposed that both alleles of this gene must be 
lost or functionally inactivated for tumorigenesis 
to occur. Although only a few such genes have 
been isolated, it has become clear that the pro- 
tein products of tumor suppressor genes play crit- 
ical roles in negatively regulating cellular prolif- 
eration. We have initiated studies to identify the 
msl gene and other functionally important genes 
whose expression is missing or altered in menin- 
giomas relative to their normal precursor cells. 
To do this, we have employed subtractive hy- 
bridization and cloning. These protocols remove 
sequences that are common to two cell popula- 
tions and enrich for sequences that are present in 
only one of these populations. Utilizing cultures 
of primary leptomeningeal cells established in 
this laboratory and two meningioma cell lines, 
we have constructed subtraction cDNA libraries 
whose cDNA contents are enriched for sequences 
of genes that are expressed in normal human lep- 
tomeningeal cells but are either not expressed or 
aberrantly expressed in meningioma tumors. 
Screening of these libraries has identified, and 
will continue to provide, candidate clones for the 
msl tumor suppressor gene and other genes of 
interest. More detailed characterization of these 
clones is in progress. 
The isolation of the msl gene and downstream 
affected genes has diagnostic and therapeutic im- 
plications for many tumors of neural crest origin. 
The availability of the leptomeningeal cell lines 
and genetic markers will provide a unique set of 
tools to begin dissection of the critical genetic 
events associated with the etiology and pathology 
of meningiomas and the elucidation of what is 
expected to be a fundamental pathway in the de- 
velopment and differentiation of multiple cell 
types in the central nervous system. 
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