Research Interests

Normal stem cells
Studies in recent years have demonstrated that stem cells exist in many somatic tissues and are active during mammalian development and homeostasis. This phenomenon is particularly well characterized in the blood-forming or hematopoietic system, where stem cells have been described in detail. By virtue of their normal biology, stem cells are generally rare. They reside at the beginning of a developmental hierarchy that generates large numbers of more differentiated progeny (see figure). Hence, while understanding stem cells is central to understanding many developmental processes, their features are often masked by more abundant cell types. The most primitive classes of stem cells are characterized by three key features. First, stem cells can recreate themselves, or “self-renew”. This central component of stem cell biology ensures a continuous supply of stem cell progeny during the lifespan of the host. Second, stem cells can typically undergo extensive proliferation. This feature is related to maintaining adequate numbers of more differentiated progeny cells. Third, stem cells are usually capable of multi-lineage differentiation. Consequently, a single stem cell can give rise to numerous distinct cell types within a specific organ/tissue.

Stem cells in cancer
The three basic properties described above make stem cells the ideal target for oncogenic events. Their natural ability to self-renew and proliferate can provide much of the fuel needed to drive tumor formation. Thus, it is a relatively short biological “leap” to go from a normal to a cancer stem cell. Indeed, mutation at the stem cell level can generate malignant cells that retain many characteristics of normal stem cells, but have lost their normal developmental regulation. Thus, while cancer stem cells may be relatively rare, they can quickly grow and differentiate into large populations of aberrant tumor cells. Importantly, recent studies have suggested that while more differentiated tumor cells may be susceptible to standard chemotherapy strategies, cancer stem cells may be resistant. Consequently, cancer stem cells may contribute to primary disease, as well as relapse following treatment.

Analysis of stem cell malignancy
Perhaps the best characterized stem cell malignancy occurs in the blood-forming tissues where damage to normal hematopoietic stem cells generates the blood cancer leukemia. A major emphasis of research in my laboratory is to understand the molecular mechanisms that control leukemic stem cells. This objective is accomplished in several ways. First, we study primary human stem cells from normal and leukemic donors as a means to directly analyze relevant molecular processes. To this end, we have developed methods by which enriched populations of leukemic stem cells can be isolated and studied using gene transfer vectors to manipulate specific genes and pathways. In addition, we have developed methods by which leukemic stem cells can be specifically destroyed while normal stem cells are spared. Elucidating the molecular mechanisms that control preferential killing of leukemic stem cells is a major emphasis in the lab. Further, we have generated mouse models of leukemic stem cells using retroviral vectors to introduce specific cancer-causing genes into normal stem cells. These model systems allow us to characterize stem cell malignancy in a detailed and step-wise fashion. In addition, such systems are exceptionally useful in the development of novel therapeutic strategies, which is also an emphasis in the lab.

Research Goals
Going forward I expect our studies to accomplish several objectives. We will generate a detailed description of the antigenic and molecular profile of leukemic stem cells. These studies will employ sophisticated flow cytometry, development of novel antibodies, and broad-based genomic and proteomic analyses. In addition, we will continue to characterize mechanisms that specifically control survival of leukemic stem cells. This effort will employ basic science approaches for pathway analysis and the development of small molecule therapeutics, as well as translational studies in collaboration with clinical faculty to develop new therapeutic strategies for acute leukemia.

1. Jordan, C.T. (2005) Targeting the most critical cells: Approaching leukemia therapy as a problem in stem cell biology. Nature Clinical Practice Oncology, 2(5):224-225.
   
2. Guzman, M.L., Rossi, R.M., Karnischky, L., Li, X., Peterson, D., Howard, D.S., and Jordan, C.T. (2005). The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood – Plenary Paper, 105(11):4163-4169.
   
3. Jordan, C.T. (2005) The potential of targeting malignant stem cells as a treatment for leukemia. Future Oncology, 1(2):1-3.
   
4. Topisirovic, I., Kentsis, A., Perez, J.M., Guzman, M.L., Jordan, C.T., and Borden, K.L. (2005). Eukaryotic translation initiation factor 4E activity is modulated by HoxA9 at multiple levels. MCB, 25(3):1100-1112.
   
5. Jordan, C.T. and Guzman, M. L. (2004) Mechanisms controlling pathogenesis and survival of leukemic stem cells. Oncogene, 23(43):7178-87.
   
6. Jordan, C.T. (2004) Cancer stem cell biology: from leukemia to solid tumors. Current Opinion in Cell Biology, 16:708-712.
   
7. Guzman, M.L., Swiderski, C.F., Grimes, B.A., Howard, D.S., Rossi, R., Szilvassy, S.J., and Jordan, C.T. (2002). Preferential induction of apoptosis for human acute myelogenous leukemia stem cells. PNAS, 99(25):16220-16225.
   
8. Jordan, C.T. (2002) Unique molecular and cellular features of acute myelogenous leukemia stem cells. Leukemia, 16(4):559-562.
   
9. Hematopoietic Stem Cell Protocols (2002), 1st Edition, by Christopher Klug and Craig T. Jordan, Methods in Molecular Medicine series, Humana Press, Totowa, New Jersey.
   
10. Guzman, M.L., Neering, S.J., Upchurch, D. Grimes, B., Howard, D.S., Rizzieri, D.A., Luger, S.M., and Jordan, C.T. (2001). NF-kB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood - Plenary Paper, 98(8):2301-2307.
    
11. Lemischka, I.R., and Jordan, C.T. (2001) The return of clonal marking sheds new light on human hematopoietic stem cells. Nature Immunology, 2(1): 11-12.
    
12. Guzman, M.L., Upchurch, D., Grimes, B., Howard, D.S., Rizzieri, D.A., Luger, S.M., Phillips, G.L., and Jordan, C.T. (2001). Expression of Tumor Suppressor Genes IRF-1 and DAP-kinase in Primitive Acute Myelogenous Leukemia Cells. Blood, 97(7):2177-2179.
    
13. Jordan, C.T., Vanin, E.F., and Marini, F.C. (2001) The use of adenoviral vectors for genetic manipulation and analysis of primitive hematopoietic cells. Current Gene Therapy, 1(3):257-266.
    
14. Jordan, C.T., Upchurch, D., Szilvassy, S.J., Guzman, M.L., Howard, D.S., Pettigrew, A.L., Meyerose, T., Rossi, R., Grimes, B., Rizzieri, D.A., Luger, S.M., and Phillips, G.L. (2000). The interleukin-3 receptor alpha chain is a unique marker for human acute leukemia stem cells. Leukemia, 14(10):1777-1784.
    
15. Howard, D.S., Rizzieri, D.A., Grimes, B., Upchurch, D., Phillips, G.L., Stewart, A.K., Yannelli, J.R., and Jordan, C.T. (1999). Genetic manipulation of primitive leukemic and normal hematopoietic cells using a novel method of adenovirus-mediated gene transfer. Leukemia, 13(10):1608-1616.
    
16. Jordan C.T. and Van Zant, G. (1998). Recent progress in identifying genes regulating stem cell function and fate. Current Opin. Cell Biol., 10:716-720.
    
17. Jordan, C.T., Minamoto, D., and Yamasaki, G. (1996). High resolution cell cycle analyses of defined phenotypic subsets within human hematopoietic cell populations. Exp. Hematol. 24:1347-1355.