Cooperation Between Mutations

It has been hypothesized that at least two somatic mutations with differing consequences collaborate to induce AML, as each alone is incapable of fully transforming a normal into a leukemic cell. These include mutations in the signal transduction pathways conferring a proliferation stimulus and mutations in genes encoding hematopoietic transcription factors that impair cell differentiation. This concept is consistent with Knudson's two-hit hypothesis, which proposes that at least two events are necessary to promote can-cer.66 This concept is important for the understanding of the mechanisms involved in leukemogenesis as well as for the development of novel treatment strategies that may have to target several dysregulated molecules in different pathways. Interestingly, simultaneous mutations of two genes cooperating in the same pathway (e.g., FLT3 and RAS) are rare.

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