Loss of TET2 Affects Proliferation and Drug Sensitivity through Altered Dynamics of Cell-State Transitions

Cell Syst. 2020 Jul 22;11(1):86-94.e5. doi: 10.1016/j.cels.2020.06.003. Epub 2020 Jul 2.

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.

Keywords: cancer; cell-state dynamics; mathematical modeling; systems biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Differentiation
  • Cell Proliferation
  • DNA-Binding Proteins / metabolism*
  • Dioxygenases
  • Humans
  • Proto-Oncogene Proteins / metabolism*

Substances

  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Dioxygenases
  • TET2 protein, human