Of mice and men...

Comment on Johnson et al, page 1334

In this issue of Blood, Johnson and colleagues describe how a recently developed transgenic mouse model of chronic lymphocytic leukemia provides an important tool for new drug development that has been missing in this disease.

There has been great progress recently in the development of murine models of leukemia and lymphoma that has been based upon more detailed knowledge of the molecular basis of these diseases. These animal models of human disease not only aid in the understanding of disease pathogenesis but also provide the necessary preclinical models to test conventional and molecularly targeted therapies. Such therapies can be tested only in strains that accurately model human leukemias and lymphomas.

New drug development in B-cell chronic lymphocytic leukemia (CLL) has been seriously hampered by both the lack of suitable cell lines derived from patients with CLL as well as appropriate animal models of the disease. The recently described Eμ-TCL1 mouse develops a B-cell lymphoproliferative disorder.¹  Flow cytometric analysis reveals a markedly expanded population of CD5⁺ B cells that are evident in the peritoneal cavity starting at 2 months of age that later become evident in the spleen and in the bone marrow. Analysis of Ig gene rearrangements indicates monoclonality or oligoclonality in these populations, indicative of a preneoplastic expansion of CD5-expressing B-cell clones, with older mice eventually developing a disorder resembling human CLL. There have certainly been concerns regarding how accurately the model reflects human CLL, questioning how useful this model might be for therapeutic studies. It remains questionable how suitable a target TCL1 will be in human CLL, and the authors point out some of the other limitations of this model, including the long latency and variability of disease development when transplanting the tumor into non–tumor-bearing mice. In this issue of Blood, Johnson and colleagues demonstrate that the CLL cells in the Eμ-TCL1 mouse model express relevant therapeutic targets, including antiapoptotic proteins, survival kinases, and DNA methyltransferases. Specifically, the TCL1 leukemia cells express Bcl-2, Mcl-1, and DNMT1, with corresponding phosphorylation of AKT and PDK1. Moreover, they also demonstrate in vitro and in vivo sensitivity to agents including fludarabine, flavopiridol, and OSU03012 and resistance to paclitaxel, as occurs in the human disease. Thus, the TCL1 transgenic leukemic cells express multiple targets relevant to human CLL and therapeutics currently being examined at Ohio State University and within the CLL Research Consortium in this disease.FIG1 

While there is naturally great excitement in exploiting strains of mice with leukemia to test therapy, these models will also be invaluable to understand mechanisms of responsiveness and resistance to chemotherapy. Although the initial response rate to fludarabine of patients with CLL is high, eventually patients develop relapse with resistant disease. Here again, Johnson and colleagues have demonstrated the utility of this murine model since these mice demonstrate initial responsiveness to fludarabine in vivo, with resulting modest improvement in survival, but rapidly develop resistant disease. Much work still has to be performed to examine the mechanisms whereby such drug resistance occurs, and in particular whether there is eventual loss of function of p53 as occurs frequently with end-stage CLL. However, this model has sufficient clinical and therapeutic similarities to human CLL to believe that this will open up exciting new opportunities to screen new drugs and novel combinations in vivo and speed therapeutic development in this still incurable disease. ▪