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Characterisation of a P140K mutant O6‐methylguanine‐DNA‐methyltransferase (MGMT)‐expressing transgenic mouse line with drug‐selectable bone marrow

Gene transfer of the P140K mutant of O6‐methylguanine‐DNA‐methyltransferase (MGMT(P140K)) into hematopoietic stem cells (HSC) provides a mechanism for drug resistance and the selective expansion of gene‐modified cells in vivo. Possible clinical applications for this strategy include chemoprotection to allow dose escalation of alkylating chemotherapy, or combining MGMT(P140K) expression with a therapeutic gene in the treatment of genetic diseases. Our aim is to use MGMT(P140K)‐driven in vivo selection to develop allogeneic micro‐transplantation protocols that rely on post‐engraftment selection to overcome the requirement for highly toxic pre‐transplant conditioning, and to establish and maintain predictable levels of donor/recipient chimerism.