| Abstract: |
A persistent puzzle in cancer biology is how mutations, which neither alter growth signaling pathways nor directly interfere with drug mechanism, can still recur and persist in tumors. One example is the mutation of the DNA demethylase tet methylcytosine dioxygenase 2 (TET2) in acute myeloid leukemias (AMLs) that frequently persists from diagnosis through remission and relapse, but whose fitness advantage in chemotherapy is unclear. Here, we use isogenic human AML cell lines to show that TET2 loss of function alters the dynamics of transitions between differentiated and stem-like states. A conceptual mathematical model and experimental validation suggest that these altered cell-state dynamics can benefit the cell population by slowing population decay during drug treatment and lowering the number of survivor cells needed to re-establish the initial population. These studies shed light on the functional and phenotypic effects of a TET2 mutation in AML and illustrate how a single gene mutation can alter a cells’ phenotypic plasticity. A record of this paper's transparent peer review process is included in the Supplemental Information. Many recurrent mutations in cancer do not directly alter growth signaling or interfere with drug mechanism, yet, are frequently observed in remission and relapse. Here, we show that one such mutation in TET2, a commonly mutated epigenetic modifier in AML, can alter switching dynamics between stem-like and differentiated cell states, enhancing population fitness. This study illustrates how one mutation can alter phenotypic plasticity and thereby provide an evolutionary strategy to promote cell population growth in and out of drug. © 2020 The Authors |
