In Vivo Model for Hematopoietic and Cancer Stem Cell Development

Background:  Although the processes of normal and cancer stem cell growth and differentiation occur in a dynamic and multi-factorial environment, study of such processes has been hindered by in vitro approximations that cannot recapitulate the complexity of actual differentiation. The best in vivo system has been the transplantation of “normal” human stem cells into mice. However, this approach has been limited by inevitable tumorigenesis. In addition, analysis was limited to a snap-shot at a specific time, as opposed to a real-time movie of an ongoing process.

Technology:  A mouse model system has been developed to allow dynamic and non-invasive analysis of normal blood cell and cancer stem cell development. This system, which involves the superposition of:

• a human gene mutation that drives erythropoietic development;
• a bioluminescent vector that can be imaged in vivo; and
• a xenogeneic mouse with high level human red blood cell (RBC) engraftment;

has been validated using sorted human embryonic stem (HES) cells. In vivo studies demonstrated solid engraftment and differentiation of cells to hematopoietic lineage with karyotypic confirmation of normalcy. Cancer stem cell development was recapitulated by transformation of normal HES cells with a gene that is necessary and sufficient for the development chronic myelogenous leukemia.

Advantages:  Real-time analysis of human blood cell development will allow one to:

• assess the efficacy of new drugs targeting hematopoietic cells and CSCs;
• determine the sequence and timing of mutations required to generate CSCs; and
• prospectively test genes required for production of lineage-specific progenitor cells from human ES cells.

 Patents pending.

Related cases: SD2007-090 and 2007-099

Research Interest:  http://cancer.ucsd.edu/summaries/cjamieson.asp & http://cancer.ucsd.edu/summaries/lgoldstein.asp

Publications:

• Jamieson CH, et. al., The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation, Proc Natl Acad Sci U S A. 2006, 103(16):6224-9.
• Clarke MF et. al. Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells, Cancer Res. 2006; 66(19):9339-44.
  Jamieson CH, et. al., Chronic versus acute myelogenous leukemia: a question of self-renewal, Cancer Cell 2004 6(6):531-3.
• Traggiai, E. et. al., Development of a human adaptive immune system in cord blood cell- transplanted mice. Science. 2004 304(5667):104-7.
• Jamieson CH, et. al., Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML, N Engl J Med. 2004 351(7):657-67.
• Passegue E, et. al., Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci U S A. 2003 100 Suppl 1:11842-9, Review.

Keywords: in vivo, HES, CSC, cancer, xenogeneic, model, drug resistance, hematopoiesis, leukemic, leukemia, biomarker, differentiation, progenitor, CML, real-time, biomarker, small molecule, drug development, screening

Case No: SD2007-241