Retroviral Transduction Models of Ph+ Leukemia: Advantages and Limitations for Modeling Human Hematological Malignancies in Mice

Abstract

There are two commonly used approaches to modeling human leukemia in mice: generation of mutant mice by traditional transgenic or knock-out/knock-in methods and retroviral bone marrow transduction and transplantation. For modeling leukemia, the retroviral model system has some distinct advantages over transgenic mice. Testing different forms and mutants of a given oncogene is much easier with the retroviral system and avoids the potential deleterious effects of expression of a transgene in nonhematopoietic tissues and during development. The retroviral provirus serves as a clonal marker of a transduced cell, facilitating analysis of clonality and transplantability of the malignancy. Finally, the retroviral system allows the assessment of the action of an oncogene in different subsets of hematopoietic precursor cells in the bone marrow, which is difficult or impossible with transgenic models. This article summarizes recent progress in modeling human Philadelphia-positive leukemia in mice with the retroviral bone marrow transduction/transplantation system and emphasizes the advantages and limitations of this approach with examples from the BCR-ABL leukemogenesis literature.

BCR-ABL-transduced human cord blood cells produce abnormal populations in immunodeficient mice

“…5 Forced expression of BCR-ABL in primitive murine hematopoietic cells results in the development of a transplantable disease that displays many of the biologic and biochemical features of human BCR-ABL þ leukemia. 6 However, an analogous model of CML based on the transplantation of BCR-ABL-transduced naïve human hematopoietic cells into suitable xenogeneic hosts has not been described previously. Here, we show that primitive human cord blood (CB) cells transduced with the same type of BCR-ABL vector found to cause leukemia in primary murine cells rapidly and durably repopulated the bone marrow (BM) of intravenously injected, nonobese diabetic-severe combined immunodeficiency (NOD/ SCID) or NOD/SCID-b2microglobulin À/À (NOD/SCID-b2m À/À ) mice.…”

Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571

“…This translocation is characterized by the formation of bcr/abl hybrid genes derived from relocation of the cabl gene from chromosome 9 to the bcr gene locus on chromosome 22. The bcr/abl hybrid genes produce BCR/ABL fusion proteins p210 and p185 kd that transform immature hematopoietic cells in vitro and cause a chronic myelogenous leukemia or acute leukemia-like syndromes in mice (Van Etten, 2001). Almost all patients with CML express the p210 BCR/ ABL protein, whereas in 50% of adults and 80% of children with Ph 1 -positive ALL the p185 BCR/ABL is detected (Faderl et al, 1999;Sawyers, 1999).…”

The molecular mechanism of chronic myelogenous leukemia and its therapeutic implications: studies in a murine model

“…Several approaches have been used to develop in vivo models for CML, including methods that introduce the BCR -ABL oncogene into the laboratory mouse genome and methods that engraft human CML cells in immunodeficient mice (reviewed in Ren, 2002;Van Etten, 2001;Wong and Witte, 2001). Generating mouse models for CML by targeting the BCR -ABL oncogene into mouse cells is important for assessing roles of both oncogenic target cells and their environments in leukemogenesis.…”

“…Three methods are generally used for targeting oncogenes into mice -transgenic, knock-in and retroviral transduction. All these approaches have been used for investigating BCR -ABL leukemogenesis (reviewed in Ren, 2002;Van Etten, 2001;Wong and Witte, 2001).…”

“…The bone marrow transduction and transplantation system has its advantages as well as limitations, as discussed elsewhere (reviewed in Ren, 2002;Van Etten, 2001). In summary this system has the following advantages.…”