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Targeting the most critical cells: approaching leukemia therapy as a problem in stem cell biology

Nature Clinical Practice Oncology volume 2, pages 224–225 (2005)Cite this article

Despite several decades of intensive effort, prognosis for most forms of myelogenous leukemia remains poor. Indeed, with the notable exceptions of all-trans retinoic acid treatment for acute promyelocytic leukemia, and imatinib therapy for chronic myelogenous leukemia (CML), standard chemotherapy regimens have not changed substantially in the past 10–15 years. While chemotherapy dose intensification and stem cell transplantation have increased long-term survival for younger and healthier patients, these options have not substantially impacted the treatment of the majority of patients with acute myelogenous leukemia (AML) and CML, most of whom are older than 60 years of age and who often have a low tolerance for high-dose chemotherapy and increased incidence of clinically significant comorbid conditions. Consequently, the basic questions of how to define and introduce better methods of leukemia therapy remain a major challenge.

Although many issues must still be resolved, recent scientific advances have provided new insights into why leukemia is such a difficult disease to treat. A variety of studies have begun to characterize the critical leukemia-initiating cell found in several forms of myeloid leukemia. Defined operationally as leukemia stem cells (LSC), these rare and specialized malignant cells arise from mutations in normal hematopoietic stem cells (HSC) or progenitor cells. Although characterization of LSC is as yet relatively limited, some important features have been described, which include a largely quiescent cell-cycle status, low frequency within the hematopoietic population, and a distinct cell-surface immunophenotype.1 Thus, LSC are biologically distinct from the bulk of leukemic blasts and may not respond predictably to standard chemotherapeutic regimens. Moreover, direct laboratory analysis has shown that LSC are refractory to both anthracycline and cytarabine treatment, the mainstays of AML chemotherapy.2 These data indicate that current regimens are unlikely to target LSC effectively in vivo. Even imatinib, a new and fundamentally different type of leukemia drug, does not appear to be active against LSC. Rather, the drug suppresses CML by ablating most malignant cells and inhibiting outgrowth from the LSC population.2 Taken together, recent studies indicate clearly that LSC-specific targeted therapies will be required to achieve more effective treatment of myelogenous leukemia.

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  1. the Director of Translation Research for Hematologic Malignancies at the James P Wilmot Cancer Center, University of Rochester, Rochester, NY, USA

    Craig T Jordan

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  1. Craig T Jordan
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Correspondence to Craig T Jordan.

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Jordan, C. Targeting the most critical cells: approaching leukemia therapy as a problem in stem cell biology. Nat Rev Clin Oncol 2, 224–225 (2005). https://doi.org/10.1038/ncponc0164

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