Granulocyte–Macrophage Progenitors as Candidate Leukemic Stem Cells in Blast-Crisis CML
Catriona H.M. Jamieson, M.D., Ph.D., Laurie E. Ailles, Ph.D., Scott J. Dylla, Ph.D., Manja Muijtjens, M.S., Carol Jones, B.A., James L. Zehnder, M.D., Jason Gotlib, M.D., Kevin Li, Ph.D., Markus G. Manz, M.D., Armand Keating, M.D., Charles L. Sawyers, M.D., and Irving L. Weissman, M.D.
Background The progression of chronic myelogenous leukemia (CML)to blast crisis is supported by self-renewing leukemic stemcells. In normal mouse hematopoietic stem cells, the processof self-renewal involves the -catenin–signaling pathway.We investigated whether leukemic stem cells in CML also usethe -catenin pathway for self-renewal.
Methods We used fluorescence-activated cell sorting to isolatehematopoietic stem cells, common myeloid progenitors, granulocyte–macrophageprogenitors, and megakaryocyte–erythroid progenitors frommarrow during several phases of CML and from normal marrow.BCR-ABL, -catenin, and LEF-1 transcripts were compared by meansof a quantitative reverse-transcriptase–polymerase-chain-reactionassay in normal and CML hematopoietic stem cells and granulocyte–macrophageprogenitors. Confocal fluorescence microscopy and a lymphoidenhancer factor/T-cell factor reporter assay were used to detectnuclear -catenin in these cells. In vitro replating assays wereused to identify self-renewing cells as candidate leukemic stemcells, and the dependence of self-renewal on -catenin activationwas tested by lentiviral transduction of hematopoietic progenitorswith axin, an inhibitor of the -catenin pathway.
Results The granulocyte–macrophage progenitor pool frompatients with CML in blast crisis and imatinib-resistant CMLwas expanded, expressed BCR-ABL, and had elevated levels ofnuclear -catenin as compared with the levels in progenitorsfrom normal marrow. Unlike normal granulocyte–macrophageprogenitors, CML granulocyte–macrophage progenitors formedself-renewing, replatable myeloid colonies, and in vitro self-renewalcapacity was reduced by enforced expression of axin.
Conclusions Activation of -catenin in CML granulocyte–macrophageprogenitors appears to enhance the self-renewal activity andleukemic potential of these cells.
Source Information
From the Division of Hematology (C.H.M.J., J.L.Z., J.G.) and the Institute of Cancer and Stem Cell Biology and Medicine, Departments of Pathology and Developmental Biology (C.H.M.J., L.E.A., S.J.D., M.M., C.J., J.L.Z., K.L., M.G.M., I.L.W.), Stanford University School of Medicine, Stanford, Calif.; Princess Margaret Hospital, University of Toronto, Toronto (A.K.); and the University of California at Los Angeles, Los Angeles (C.L.S.).
Address reprint requests to Dr. Weissman at the Department of Pathology, Stanford University School of Medicine, B257 Beckman Center, 279 Campus Dr., Stanford, CA 94305-5323, or at ljquinn{at}stanford.edu.
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Nakanishi, T., Shiozawa, K., Hassel, B. A., Ross, D. D.
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Koptyra, M., Falinski, R., Nowicki, M. O., Stoklosa, T., Majsterek, I., Nieborowska-Skorska, M., Blasiak, J., Skorski, T.
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Jamieson, C. H. M., Gotlib, J., Durocher, J. A., Chao, M. P., Mariappan, M. R., Lay, M., Jones, C., Zehnder, J. L., Lilleberg, S. L., Weissman, I. L.
(2006). The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation. Proc. Natl. Acad. Sci. USA
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Notari, M., Neviani, P., Santhanam, R., Blaser, B. W., Chang, J.-S., Galietta, A., Willis, A. E., Roy, D. C., Caligiuri, M. A., Marcucci, G., Perrotti, D.
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Luckey, C. J., Bhattacharya, D., Goldrath, A. W., Weissman, I. L., Benoist, C., Mathis, D.
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Radich, J. P., Dai, H., Mao, M., Oehler, V., Schelter, J., Druker, B., Sawyers, C., Shah, N., Stock, W., Willman, C. L., Friend, S., Linsley, P. S.
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[Abstract][Full Text]
-catenin–signaling pathway. We investigated whether leukemic stem cells in CML also use the 
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