hasvector.blogg.se

It is known, for example, that secondary hematopoietic malignancies, such as acute myeloid leukemia (AML) occur in patients who are exposed to chemotherapies as part of the treatment of a solid malignancy 11, 12. One homeostatic process in which the long-term effects of chemotherapies have been extensively studied is hematopoiesis. Some widely used chemotherapies, due to their mutagenic mechanism, also contribute to the genetic variation present in exposed tumor cells or cell lines 5, 6, 7, 8, 9, 10. Certain cells, able to withstand chemotherapies by virtue of certain advantageous mutations or phenotypic characteristics may subsequently expand to replenish the exhausted tissue after the insult is withdrawn. Chemotherapies cause the death of large amounts of cells, thus imposing specific selective constraints on somatic tissues 4. Somatic tissues evolve as a result of the interplay between genetic variation-contributed by a range of endogenous and external mutational processes-and selective constraints acting at the level of organs or tissues 1, 2, 3. Its absence in clonal hematopoiesis cases is consistent with the start of the clonal expansion predating the exposure to platinum-based drugs.

Using the platinum-based mutational signature as a barcode, we determine that the clonal expansion originating the secondary AMLs begins after the start of the cytotoxic treatment. No trace of the 5-fluorouracil (5FU) mutational signature is found in AMLs secondary to exposure to 5FU, suggesting that cells establishing the leukemia could be quiescent during treatment. Cells of Acute Myeloid Leukemia (AML) secondary to treatment with platinum-based drugs show the mutational footprint of these drugs, indicating that non-malignant blood cells receive chemotherapy mutations. Here, exploiting the mutational footprint of some chemotherapies, we explore their influence on the evolution of hematopoietic cells. However, their contributions to the mutation burden and clonal expansions of healthy somatic tissues are not clear.

Chemotherapies may increase mutagenesis of healthy cells and change the selective pressures in tissues, thus influencing their evolution.