The central focus of our research is to search for selective targetable differences between normal and CML quiescent stem cells. We chose CML because highly effective bcr-abl inhibitors are available that can eliminate the great majority of proliferating cells in early stage disease with relatively little toxicity. However, these drugs are not curative, probably because the quiescent CML stem cells are resistant to these drugs as well as to most other drugs. We have isolated highly purified subpopulations of proliferating and quiescent normal and CML stem and progenitor cells. In quiescent (CD34+/GO) normal but not CML cells compared to cycling cells (CD34+/G1SG2M) there is down-regulation of CD38 and up-regulation of stem cell-associated genes including ALDH, HLF, and GATA3. In comparing CML and normal CD34+/GO cells, a number of stem cell associated genes are down-regulated in CML GO cells, including CD133 (↓20 fold),. MSI2, HLF, GBP2, and DLG7, and there is up-regulation of genes characteristic of erythro-megakaryocyte development (CD36, KLF-Hemoglobin , , , TFR2 and CD41, providing additional evidence that the majority of GO CML cells belong to a more differentiated compartment than the normal GO cells. Of the up-regulated genes, the Ra isoform of LepR is one of the most over-expressed genes (20 fold), and, being a receptor, it might be used to distinguish quiescent CML cells from normal ones and possibly serve as a target for a drug or armed antibody. We are currently further enriching and characterizing normal and CML stem cells (i.e. CD34+CD38-Thy1+CD45RA-) and examining other differences in signaling molecules and pathways (e.g. CD133, Akt-FOXO, PI3K, lipid raft formation) that may explain why CML stem cells continue cycling and producing cells long beyond normal homeostatic limits. If we are successful in identifying targetable differences and developing effective selective drugs for quiescent CML stem/progenitor cells, it is likely this research will be applicable to other types of cancer.
Clarkson B, Strife A, Wisniewski D, Lambek CL, and Liu C: Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies. Leukemia 17:1211-1262, 2003.
Nagar B, Hantschel O, Young MA, Scheffzek K, Veach D, Bornmann W, Clarkson B, Superti-Furga G, and Kuriyan J. Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell 112:859-871, 2003.
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