By Hien Duong, MD, and Mikkael A. Sekeres, MD, MS

2009-12-06

The concept of leukemia stem cells (LSCs) is receiving a great deal of attention, especially because of the potential role of LSCs in therapeutic success or failure in conditions such as acute myeloid leukemia (AML). LSCs were the focus of yesterday afternoon’s Scientific Program Session on myeloid neoplasia.

Dr. John E. Dick from the University Health Network in Toronto, the recipient of this year’s E. Donnall Thomas Prize, set the tone for the session during his discussion of the elusive nature of the LSC.  Dr. Dick described LSCs as a distinct subset of cells responsible for the long-term survival and maintenance of tumor growth. While the majority of leukemic blasts are generated from a rapidly proliferating subset of leukemic cells, there is another subset of cells, thought to be quite rare, that are quiescent and may only divide once every few weeks or months. Despite their apparent rarity, these LSCs are capable of producing AML colony-forming units (AML-CFU) and leukemic blasts. In xenograft models, transduction of one LSC versus a higher number of LSCs resulted in different karyotypic phenotypic changes. LSCs also have other distinct properties, including resistance to conventional chemotherapy and an abnormal response to apoptosis-inducing stimuli.

How rare are LSCs?  The conventional view, derived from various xenograft models, is that the frequency of LSC varies among myeloid maligancies, but they constitute <1 percent of neoplastic cells and perhaps as few as <1 in 106 cells, with the highest number seen within certain AML subtypes, such as those with rearrangements of the MLL gene. Dr. Michael Cleary from Stanford University challenged this conventional view with the “revisionist view.” Dr. Cleary presented evidence that in some malignancies, LSCs may be more frequent than previously suspected and may have lineage-specific features. In an AML mouse model of MLL-associated leukemia, LSCs were remarkably prevalent, accounting for almost one-quarter of malignant cells, although this did not necessarily predict for more efficient engraftment. LSCs are organized in a phenotypic and functional hierarchy, expressing myeloid lineage-specific antigens ordinarily not seen in hematopoietic progenitor cells. In fact, LSCs may actually be more mature myeloid lineage-specific cells that have aberrantly acquired self-renewal features, along with other stem cell properties. 

But what do we really know about LSCs, and how can we learn more about them? Dr. Craig Jordan from the University of Rochester discussed the current experimental techniques and preclinical models that are available to investigators. These model systems indicate that LSCs in different myeloid malignancies have variable phenotypes, frequencies, cell cycle status, and drug responsiveness. Moreover, LSCs can evolve and become unstable throughout the disease course, making them complicated targets. It is difficult to predict whether LSC responses to drug therapy in pre-clinical models will translate to similar responses in patients. 

Despite these limitations, there is evidence that specifically targeting LSCs can lead to improved outcomes. Current therapeutic investigations include LSC-directed monoclonal antibodies, small molecules that block self-renewal pathways, immunotherapeutic approaches, and other methods of targeting leukemia-specific survival strategies in a way that is not dependent on the cell entering the cell cycle.

So what’s so great about LSCs? LSCs are the only leukemic cells capable of self-renewal, while still being able to generate proliferating progenitors and terminal leukemic blasts. This property, coupled with their resistance to standard chemotherapy and other biologic properties, makes them the seeds of relapse in AML and other myeloid neoplasms. Regardless of whether they are rare or abundant, whether they vary in properties from one myeloid malignancy to another, or how they evolve during the course of the disease, the future of successful leukemia therapy may hinge on eradication of LSCs.

If you weren’t able to attend yesterday’s session, you can catch this session this morning from 9:30 to 11:00 a.m. in rooms R06-R09 of the Morial Convention Center.

Drs. Duong and Sekeres indicated no relevant conflicts of interest.

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