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A review of the mutagenic potential of N‐ethyl‐N‐nitrosourea (ENU) to induce hematological malignancies

This review is intended to summarize the existing literature on the mutagenicity of N‐ethyl‐N‐nitrosourea (ENU) in inducing hematological malignancies, including acute myeloid leukemia (AML) in mice. Blood or hematological malignancies are the most common malignant disorders seen in people of all age groups. Driven by a number of genetic alterations, leukemia rule out the normal proliferation and differentiation of hematopoietic stem cells (HSCs) and their progenitors in the bone marrow (BM) and severely affects blood functions. Out of all hematological malignancies, AML is the most aggressive type, with a high incidence and mortality rate. AML is found as either de novo or secondary therapeutic AML (t‐AML). t‐AML is a serious adverse consequence of alkylator chemotherapy to the cancer patient and alone constitutes about 10%−20% of all reported AML cases. Cancer patients who received alkylator chemotherapy are at an elevated risk of developing t‐AML. ENU has a long history of use as a potent carcinogen that induces blood malignancies in mice and rats that are pathologically similar to human AML and t‐AML. ENU, once entered into the body, circulates all over the body tissues and reaches BM. It creates an overall state of suppression within the BM by damaging the marrow cells, alkylating the DNA, and forming DNA adducts within the early and late hematopoietic stem and progenitor cells. The BM holds a weak DNA repair mechanism due to low alkyltransferase, and poly [ADP‐ribose] polymerase (PARP) enzyme content often fails to obliterate those adducts, acting as a catalyst to bring genetic abnormalities, including point gene mutations as well as chromosomal alterations, for example, translocation and inversion. Taking advantage of ENU‐induced immune‐suppressed state and weak immune surveillance, these mutations remain viable and slowly give rise to transformed HSCs. This review also highlights the carcinogenic nature of ENU and the complex relation between the ENU's overall toxicity in the induction of hematological malignancies.