The objective of this application is to map the population dynamics of the myeloma clone throughout disease with particular emphasis on pre-switch members of the MM hierarchy. Genetic markers will be used to indirectly monitor precursor function through analysis of clonal emergence, clonal expansion, clonal extinction and/or clonal dominance in MM during and after therapy, and to determine the clinical impact of MM clonal variants. This application will begin analysis of the biological role of pre-switch cells within the MM clone. It is based on the hypotheses that the MM clone is heterogeneous, with precursor function residing throughout the MM hierarchy, that a significant component of stem cell function resides in pre-switch MM cells, and that switch region translocations are secondary events in MM, associated with disease progression rather than disease origins, and that if an MM clonal variant underlies more aggressive disease, over time it will emerge as the dominant clone.
Specific aims are: 1. To characterize pre-switch clonotypic MM cells in sorted B lineage subsets from blood and via laser capture of physically, morphologically and/or phenotypically identified BM cells together. To monitor BM-localized pre-switch MM cells throughout the course of MM. To determine the ability of MM subsets enriched in cells expressing pre-switch clonotypic transcripts to xenograft the MM clone to NOD SCID mice. 2. To use the t (4;14) translocation, identified by the presence of IgH-MMSET fusion transcripts, as a genetic marker to follow population dynamics within the MM clone throughout the course of disease. To determine the extent of heterogeneity within the MM clone using analysis of cell populations captured from defined locations in MM BM. To determine whether response to therapy is accompanied by clonal extinction and/or if disease progression is accompanied by clonal expansion of MM variants, based on longitudinal analysis of clonotypic lgH VDJ and IgH-MSET transcripts at diagnosis, during remissions, in relapse and at terminal stages of disease. To determine whether the t(4;14) translocation confers a growth advantage on MM precursor cells. 3. To begin to define why persistent expression of pre-switch clonotypic transcripts correlates with reduced survival by determining the basis for the expression of pre-switch transcripts and the potential role of class switching in MM. This may lead to improvements in therapy and survival for myeloma patients.
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