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Review
. 2016 Apr;43(2):222-32.
doi: 10.1053/j.seminoncol.2016.02.007. Epub 2016 Feb 8.

Preclinical modeling of novel therapeutics in chronic lymphocytic leukemia: the tools of the trade

Sarah E M Herman  1 , Adrian Wiestner  2
Affiliations
Review

Preclinical modeling of novel therapeutics in chronic lymphocytic leukemia: the tools of the trade

Sarah E M Herman et al. Semin Oncol. 2016 Apr.

Abstract

In the last decade our understanding of chronic lymphocytic leukemia (CLL) biology and pathogenesis has increased substantially. These insights have led to the development of several new agents with novel mechanisms of action prompting a change in therapeutic approaches from chemotherapy-based treatments to targeted therapies. Multiple preclinical models for drug development in CLL are available; however, with the advent of these targeted agents, it is becoming clear that not all models and surrogate readouts of efficacy are appropriate for all drugs. In this review we discuss in vitro and in vivo preclinical models, with a particular focus on the benefits and possible pitfalls of different model systems in the evaluation of novel therapeutics for the treatment of CLL.

Keywords: Chronic lymphocytic leukemia; Co-culture systems; Mouse models.

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Conflict of interest statement

Conflict-of-Interest Disclosure:

All authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Recapitulation of the CLL tissue microenvironment in vitro
In vivo CLL cells receive signals from multiple cell types leading to cellular activation, proliferation and survival. This can be recreated in vitro by the addition of accessory cells such as stromal cells, NLCs or other PBMC subsets (represented in green) that alter CLL cell signaling through either direct cell-cell contact or through the release of cytokines or chemokines such as IL-4, IL-8 or CXCL12. Additionally, CLL cell activation and signal transduction that occurs in the microenvironment can be replicated by the addition of soluble factors (represented in red) such as anti-IgM, which ligates the B-cell Receptor (BCR), CpG-ODN, which activates toll-like receptor 9 (TLR9) in endosomes, or cytokines such as sCD40L or IL-4. Binding of these soluble factors to their respective receptors leads to activation of key CLL signaling pathways, including BCR, PI3K, NF-κB and JAK/STAT, leading to a multitude of downstream events including the up-regulation of pro-survival proteins (such as MCL-1, BCL-2, XIAP and survivin).
Figure 2
Figure 2. Recreation of the human lymph node microenvironment in the spleen of NSG mice
(A) PBMCs were collected from the lymph node (hLB) or the peripheral blood (hPB) of patients with CLL. PBMCs from the hPB were then xenografted into NSG mice. After 3 weeks human PBMCs were recollected from the mouse peripheral blood (mPB) or the mouse spleen (mSP). (B) CLL cells collected from the mouse or the human microenvironment display similar expression of BCR and NF-κB gene signatures (the average of validated BCR and NF-κB target genes) (B) surface activation markers CD38, CD69 and CXCR4 (C) and proliferation (D) compared to peripheral blood (PB). All readouts were significantly increased in both microenvironments compared to peripheral blood (P<0.05), but there was no significant difference between the up-regulation induced by the mouse spleen and the human lymph node; statistics done by student t-test. All data is shown as the mean ± SEM normalized to matched peripheral blood. Adapted from Herman et al.
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