Preclinical approaches in chronic myeloid leukemia: from cells to systems

Abstract

Advances in the design of targeted therapies for the treatment of chronic myeloid leukemia (CML) have transformed the prognosis for patients diagnosed with this disease. However, leukemic stem cell persistence, drug intolerance, drug resistance, and advanced-phase disease represent unmet clinical needs demanding the attention of CML investigators worldwide. The availability of appropriate preclinical models is essential to efficiently translate findings from the bench to the clinic. Here we review the current approaches taken to preclinical work in the CML field, including examples of commonly used in vivo models and recent successes from systems biology-based methodologies.

Figure 1

CML disease progression. The majority of CML patients are diagnosed in the chronic phase, which will progress through the accelerated phase to blast crisis if untreated. Each phase can be characterized by the number of immature cells (blasts) found in the BM. Expression of BCR-ABL activates a number of signaling pathways, resulting in increased proliferation and decreased apoptosis in the myeloid compartment. Secondary genetic and molecular abnormalities lead to an accumulation of mutations and genomic instability, resulting in progression to blast crisis and poor patient prognosis.

Figure 2

Schematic representation of the three mouse models of CML. The three main mouse models of CML are described, including variations described in the literature and commonly performed downstream analysis. (A) Retroviral model: Donor mice are treated with 5-FU; BM cells are collected and treated with BCR-ABL retrovirus produced from HEK293 cells; and transduced cells are transplanted into irradiated recipients. (B) SCLtTA/BCR-ABL transgenic model: BM is isolated from SCLtTA/BCR-ABL donors and transplanted into irradiated recipients, with BCR-ABL expression being inducibly expressed in the stem and progenitor cells on removal of tetracycline from the drinking water. (C) Xenograft model: CD34⁺ CML cells are isolated from patient material and transplanted into immunocompromised recipient mice.