Hematopoietic stem cells (HSCs) are unique in their ability to self-renew and generate all blood lineages for the entire life. HSC modification affects red blood cells, platelets, lymphocytes, and myeloid cells. Chemotherapy can result in myelosuppression, limiting effective chemotherapy administration. For diseases like glioblastoma, high expression of methlylguanine methyltransferase can inactivate alkylating agent chemotherapy. Here we discuss how HSCs can be modified to overcome this resistance, permitting sensitization of tumors to chemotherapy while simultaneously protecting the hematopoietic system. We also discuss how HSCs can be harnessed to produce powerful tumor killing T cells, potentially benefitting and complementing T-cell–based immunotherapies.
Key points
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Cancers with high expression of methlylguanine methyltransferase (MGMT) have a worse prognosis owing to resistance to temozolomide (TMZ) treatment, especially for glioblastoma.
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O 6 -benzylguanine (O 6 BG) is effective in reversing MGMT-mediated chemotherapy resistance but renders hematopoietic cells highly susceptible to TMZ-associated toxicities.
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The P140K mutant MGMT does not bind O 6 BG and thus when expressed in blood cells can make them resistant to the combination therapy O 6 BG and temozolomide.
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Combination O 6 BG and TMZ treatment improves survival in glioblastoma and potentially other cancers with high expression of MGMT.
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Hematopoietic stem cells (HSCs) can also be targeted to produce T cells expressing engineered T-cell receptors and chimeric antigen receptors for immunotherapy.
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