ABMT is harvested in marrow remission when - by definition - no malignant 
cells are detectable. It is therefore impossible to undertake any form of 
quality control to determine if residual malignant cells have genuinely been 
eliminated. Moreover, there is no evidence that malignant cells with the 
ability to reestablish the malignancy after ABMT are physically, phenotypically, 
or biochemically identical to the cells of the "mature" tumor. At present, 
therefore, the justification for and practicality of bone marrow purging largely 
remain matters of faith. This is cause for considerable concern. The 
techniques of purging almost invariably damage normal progenitor cells, so 
that the engraftment of purged marrow is generally substantially slower than 
the engraftment of untreated marrow. Morbidity and mortality from the 
complications of hemopoietic and immune system failure are correspondingly 
increased. 
2.4 Biology of Autologous Reconstitution 
Little is known in man of the fundamental biology of autologous marrow graft 
recovery. It is unknown whether the cryopreserved marrow contains viable 
stem cells which subsequently reconstitute the patient, or whether the 
autograft simply provides temporary replenishment of committed progenitor 
cells whilst surviving host stem cells gradually repopulate the individual. If 
harvested marrow does contain stem cells, nothing is known of the in vivo 
signals which modify their entry into cell cycle or which modulate proliferation 
versus lineage commitment. This lack of knowledge hampers efforts to 
improve the speed and effectiveness with which autologous marrow 
reconstitutes the patient. Even though large volumes of marrow may be taken, 
patients may still suffer prolonged marrow hypoplasia and immune 
dysfunction. If ABMT cures patients by virtue of the more intensive chemo- 
radiotherapy it permits, then multiple ABMT might cure a higher proportion 
of patients. This approach cannot readily be contemplated until techniques 
which improve marrow regeneration are available, as the procedure related 
morbidity and mortality would otherwise be unacceptably high. 
3.0 RATIONALE FOR CURRENT PROPOSAL 
3.1 Gene Markers for Autologous Marrow 
Because autologous marrow is phenotypically and genetically identical to 
residual host tissues, it has not been possible to date to investigate either the 
source of malignant relapse following ABMT in malignancies which are 
derived from or involve the bone marrow or the mechanisms of marrow 
regeneration after the procedure (Section 3.3). The availability of transduction 
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Recombinant DNA Research, Volume 14 
