Structural and diffusion weighted MRI demonstrates responses to ibrutinib in a mouse model of follicular helper (Tfh) T-cell lymphoma

PLoS One. 2019 Apr 23;14(4):e0215765. doi: 10.1371/journal.pone.0215765. eCollection 2019.

Abstract

Recent analyses of the genetics of peripheral T-cell lymphoma (PTCL) have shown that a large proportion of cases are derived from normal follicular helper (Tfh) T-cells. The sanroque mouse strain bears a mutation that increases Tfh cell number and heterozygous animals (Roquinsan/+) develop lymphomas similar to human Tfh lymphoma. Here we demonstrate the usefulness of Roquinsan/+ animals as a pre-clinical model of Tfh lymphoma. Long latency of development and incomplete penetrance in this strain suggests the lymphomas are genetically diverse. We carried out preliminary genetic characterisation by whole exome sequencing and detected tumor specific mutations in Hsp90ab1, Ccnb3 and RhoA. Interleukin-2-inducible kinase (ITK) is expressed in Tfh lymphoma and is a potential therapeutic agent. A preclinical study of ibrutinib, a small molecule inhibitor of mouse and human ITK, in established lymphoma was carried out and showed lymphoma regression in 8/12 (67%) mice. Using T2-weighted MRI to assess lymph node volume and diffusion weighted MRI scanning as a measure of function, we showed that treatment increased mean apparent diffusion coefficient (ADC) suggesting cell death, and that change in ADC following treatment correlated with change in lymphoma volume. We suggest that heterozygous sanroque mice are a useful model of Tfh cell derived lymphomas in an immunocompetent animal.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives
  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Disease Models, Animal
  • Drug Evaluation, Preclinical / methods
  • Heterozygote
  • Humans
  • Lymph Nodes / cytology
  • Lymph Nodes / diagnostic imaging
  • Lymph Nodes / drug effects
  • Lymphoma, T-Cell, Peripheral / diagnostic imaging
  • Lymphoma, T-Cell, Peripheral / drug therapy*
  • Lymphoma, T-Cell, Peripheral / genetics
  • Magnetic Resonance Imaging
  • Mice
  • Piperidines
  • Primary Cell Culture
  • Pyrazoles / administration & dosage*
  • Pyrimidines / administration & dosage*
  • T-Lymphocytes, Helper-Inducer / drug effects
  • T-Lymphocytes, Helper-Inducer / pathology
  • Treatment Outcome
  • Tumor Cells, Cultured
  • Ubiquitin-Protein Ligases / genetics

Substances

  • Antineoplastic Agents
  • Piperidines
  • Pyrazoles
  • Pyrimidines
  • ibrutinib
  • Rc3h1 protein, mouse
  • Ubiquitin-Protein Ligases
  • Adenine

Grants and funding

The work was in part supported by a grant from Janssen who also provided Ibrutinib. RLA was supported by a clinical research fellowship from the Ernest and Helen Scott Haematology Research Institute and SM was supported by a PhD studentship from the Government of Iraq. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.