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PML/RARa leukemia induced murine model for immunotherapy evaluation.

Rodrigo N Shiraishi1, André L Bombeiro2, Tamara C L Castro3

  • 1Hematology and Transfusion Medicine Center - Hemocentro, University of Campinas, 13083-878 Campinas, São Paulo, Brazil.

Transplant Immunology
|August 20, 2023
PubMed
Summary

This study establishes a novel acute promyelocytic leukemia (PML/RARa) model in immunocompetent mice, enabling the investigation of drug-induced cellular immune responses. The model effectively mimics leukemia progression and shows promise for preclinical drug development studies.

Keywords:
BALB/cImmunocompetent miceMurine leukemia modelPML/RARa

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Area of Science:

  • Hematology and Oncology
  • Immunology
  • Preclinical Drug Development

Background:

  • Existing leukemia murine models often utilize immunocompromised mice, limiting the study of immune responses.
  • There is a need for reliable models in immunocompetent hosts to study leukemia's interaction with the immune system.

Purpose of the Study:

  • To establish and validate a transplantation-based acute promyelocytic leukemia (PML/RARa) model in immunocompetent BALB/c mice.
  • To assess the utility of this model for investigating drug-induced cellular immune responses in leukemia.

Main Methods:

  • Establishment of a PML/RARa leukemia model via transplantation in BALB/c mice.
  • Confirmation of leukemia development through hematological analysis (leukocytosis, anemia, thrombocytopenia) and peripheral blood blast counts.
  • Flow cytometry and in vivo imaging to analyze immune cell populations (T lymphocytes, NK cells, B cells, neutrophils, monocytes) and macrophage polarization in bone marrow, peripheral blood, and spleen.
  • Evaluation of all-trans retinoic acid (ATRA) treatment effects on leukemia progression and immune cell profiles.

Main Results:

  • Successful induction of PML/RARa leukemia characterized by significant hematological alterations and increased immature cells/promyelocytes in bone marrow, peripheral blood, and spleen.
  • Distinct changes in immune cell frequencies, including alterations in T lymphocytes, NK cells, B cells, neutrophils, and monocytes, were observed.
  • ATRA treatment effectively reduced blasts and promyelocytes in bone marrow and spleen, and increased peripheral blood neutrophils, validating the model's responsiveness to therapy.

Conclusions:

  • The developed PML/RARa leukemia model in immunocompetent BALB/c mice is a cost-effective and reliable tool for studying leukemia.
  • This model facilitates the investigation of drug-induced cellular immune responses, crucial for advancing leukemia therapeutics.
  • The model's responsiveness to ATRA treatment underscores its potential for preclinical drug development and efficacy testing.