Detection of residual and chemoresistant leukemic cells in an immune-competent mouse model of acute myeloid leukemia: Potential for unravelling their interactions with immunity

PLoS One. 2022 Apr 29;17(4):e0267508. doi: 10.1371/journal.pone.0267508. eCollection 2022.

Abstract

Acute myeloid leukemia (AML) is characterized by blocked differentiation and extensive proliferation of hematopoietic progenitors/precursors. Relapse is often observed after chemotherapy due to the presence of residual leukemic cells, which is also called minimal residual disease (MRD). Subclonal heterogeneity at diagnosis was found to be responsible for MRD after treatment. Patient xenograft mouse models are valuable tools for studying MRD after chemotherapy; however, the contribution of the immune system in these models is usually missing. To evaluate its role in leukemic persistence, we generated an immune-competent AML mouse model of persistence after chemotherapy treatment. We used well-characterized (phenotypically and genetically) subclones of the murine C1498 cell line stably expressing the ZsGreen reporter gene and the WT1 protein, a valuable antigen. Accordingly, these subclones were also selected due to their in vitro aracytidine (Ara-c) sensitivity. A combination of 3 subclones (expressing or not expressing WT1) was found to lead to prolonged mouse survival after Ara-c treatment (as long as 150 days). The presence of residual leukemic cells in the blood and BM of surviving mice indicated their persistence. Thus, a new mouse model that may offer insights into immune contributions to leukemic persistence was developed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytarabine / pharmacology
  • Cytarabine / therapeutic use
  • Disease Models, Animal
  • Disease Progression
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Leukemia, Myeloid, Acute* / genetics
  • Mice
  • Neoplasm, Residual / diagnosis

Substances

  • Cytarabine

Grants and funding

We are grateful to SIRIC ONCOLille (Grant INCa-DGOS-Inserm 6041) and CPER (Contrat de Plan Etat-Region) Cancer 2015-2020 for supporting this study. We also acknowledge the CHU of Lille and the Region Hauts-de-France as well as the University of Lille for respective funding of Alexia Mopin and Meriem Ben Khoud, PhD graduate students. Conceptualization, C.B. (animal model), F.L and M.F. (genomics); methodology and experimentation, A.M., M.B.K., S.S., C.V.; writing—original draft preparation, A.M., C.B. and F.L.; writing—review and editing, C.B.; visualization, A.M., F.L. and C.B.; supervision, C.B. and M.F.; project administration, C.B. and B.Q.; funding acquisition, C.B. and B.Q. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.