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Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies

Leukemia volume 17, pages 1211–1262 (2003)Cite this article

Abstract

The chronological history of the important discoveries leading to our present understanding of the essential clinical, biological, biochemical, and molecular features of chronic myelogenous leukemia (CML) are first reviewed, focusing in particular on abnormalities that are responsible for the massive myeloid expansion. CML is an excellent target for the development of selective treatment because of its highly consistent genetic abnormality and qualitatively different fusion gene product, p210bcr-abl. It is likely that the multiple signaling pathways dysregulated by p210bcr-abl are sufficient to explain all the initial manifestations of the chronic phase of the disease, although understanding of the circuitry is still very incomplete. Evidence is presented that the signaling pathways that are constitutively activated in CML stem cells and primitive progenitors cooperate with cytokines to increase the proportion of stem cells that are activated and thereby increase recruitment into the committed progenitor cell pool, and that this increased activation is probably the primary cause of the massive myeloid expansion in CML. The cooperative interactions between Bcr-Abl and cytokine-activated pathways interfere with the synergistic interactions between multiple cytokines that are normally required for the activation of stem cells, while at the same time causing numerous subtle biochemical and functional abnormalities in the later progenitors and precursor cells. The committed CML progenitors have discordant maturation and reduced proliferative capacity compared to normal committed progenitors, and like them, are destined to die after a limited number of divisions. Thus, the primary goal of any curative strategy must be to eliminate all Philadelphia positive (Ph+) primitive cells that are capable of symmetric division and thereby able to expand the Ph+ stem cell pool and recreate the disease. Several highly potent and moderately selective inhibitors of Bcr-Abl kinase have recently been discovered that are capable of killing the majority of actively proliferating early CML progenitors with minimal effects on normal progenitors. However, like their normal counterparts, most of the CML primitive stem cells are quiescent at any given time and are relatively invulnerable to the Bcr-Abl kinase inhibitors as well as other drugs. We propose that survival of dormant Ph+ stem cells may be the most important reason for the inability to cure the disease during initial treatment, while resistance to the inhibitors and other drugs becomes increasingly important later. An outline of a possible curative strategy is presented that attempts to take advantage of the subtle differences in the proliferative behavior of normal and Ph+ stem cells and the newly discovered selective inhibitors of Bcr-Abl.

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Acknowledgements

We thank Pfizer Global Research and Development (Ann Arbor Laboratories, MI 48105-2430, USA), formerly Parke-Davis Pharmaceutical Research (Division of the Warner-Lambert Co., Ann Arbor, MI 48105, USA) and Dr Neal Rosen for initially providing PD173955, Dr Nicholas Lydon and Novartis Inc. (Basel, Switzerland) for initially providing STI571 (formerly known as CGP57148B), Dr Brian Druker, University of Oregon for giving us the M07e and M07e/p210bcr-abl cell lines, and the Kirin Brewery Company, Limited (Tokyo, Japan) for their generosity in supplying rhG-CSF, rhGM-CSF, rhIL-3, rhKL, and rhSCF. We also thank our collaborators: Dr William G Bornmann and Dr Darren Veach at MSKCC's Preparative Synthesis Laboratory for synthesizing PD173955, PD166326 and other compounds and helpful discussions; Dr John Kuriyan, Drs Bhushan Nagar, Thomas Schindler, Holger Sonderman, and Matthew Young at Rockefeller University, New York, and the University of California, Berkeley, for cocrystallizing the inhibitors with abl kinase and for helpful discussions. We are also grateful to Dr Richard T Silver, Emeritus Director, Clinical Oncology Chemotherapy Research, Division of Hematology and Medical Oncology, New York Presbyterian Cornell Medical Center, and his Nursing and Office Staff for their assistance in obtaining samples of CML blood and marrow, especially Ms Eugenie Balam. We are especially grateful to Su De Meritt for her extensive work in preparing the manuscript. This research was supported by National Cancer Institute (NCI) Grant CA64593 and NCI Cancer Center Support Grant CA08748, The Albert C Bostwick Foundation, The Enid A Haupt Charitable Trust, The Andrew Sage Trust, The Einard and Sue Sundin Fund, The United Leukemia Fund, The Carley H Wagner Trust, The Westvaco Corporation and MeadWestvaco.

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  1. Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute for Cancer Research, New York, NY, USA

    B Clarkson, A Strife, D Wisniewski, C L Lambek & C Liu

  2. Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    B Clarkson

  3. Department of Medicine, Weill Medical College, Cornell University, New York, NY, USA

    B Clarkson

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  1. B Clarkson
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Clarkson, B., Strife, A., Wisniewski, D. et al. Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies. Leukemia 17, 1211–1262 (2003). https://doi.org/10.1038/sj.leu.2402912

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