Many B-cell cancers that arise during the maturation of B lymphocytes in germinal centers over express AID (activation-induced deaminase) which converts cytosine in DNA to uracil. We have previously shown that B-cell lymphoma cell lines and patient tumors express AID at high levels and contain elevated levels of uracil in their genome. Their attempt to remove excess uracils through the base excision repair pathway result high levels of abasic (AP) sites in their genome. AP sites exist in equilibrium with the open form of deoxyribose sugar containing a reactive aldehyde group that reacts with alkoxyamines forming a stable oxime. This principle could be used to block the repair of excess AP sites and kill B cell cancers. We found three alkoxyamines with an alkyne functional group that covalently link to abasic sites in DNA and kill B-cell lymphoma derived cell lines but not other cancers. Also these alkoxyamine-DNA adducts cause cell death by blocking the progression of the DNA replication fork and elevate DNA breaks. However, other alkoxyamines that lack the alkyne functionality do not kill B cell lymphoma derived cell lines although they covalently link to DNA. This indicates that the ability of alkoxyamines to covalently link to the abasic sites is insufficient for the killing and the alkyne functionality which is considered bioorthogonal (unreactive towards biomolecules), plays a major role in it. In future we are planning to elucidate the molecular mechanism of cell killing by these novel alkoxyamines and develop strategies to increase its efficacy of killing cancers.

Novel class of chemicals that react with abasic sites in DNA and specifically kill B cell cancers

2019 Spring National Meeting

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