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April 16, 2010

Bringing leukemia out of hiding

Two new strategies target a deadly cancer that eludes conventional chemotherapy

Figure 1: AML (left) can initially be driven into remission with chemotherapy, but this leaves behind a subpopulation of resistant LSCs (middle), with a high potential for initiating a fatal relapse (top right). Complete elimination of AML from patients may eventually be possible by directly targeting LSCs through more effective chemotherapeutic strategies or the identification of clinically useful LSC-specific markers (bottom right).

© 2010 Fumihiko Ishikawa

Acute myeloid leukemia (AML) is the most common form of adult leukemia, and with an estimated five-year survival rate of 20%, the long-term prognosis for many patients is relatively grim.

“Current treatments for AML can initially reduce the number of AML cells to undetectable levels, a state referred to as ‘complete remission’,” says Fumihiko Ishikawa of the RIKEN Research Center for Allergy and Immunology in Yokohama. “Unfortunately, in a substantial proportion of these patients, AML eventually comes back—and many that relapse succumb to the disease.” The need for an improved arsenal to fight AML has guided much of Ishikawa’s work, and two recently published articles from his team present promising strategies for tackling this dreaded cancer.

AML originates in bone marrow, and relapse is initiated from small pockets of chemotherapy-resistant ‘leukemia stem cells’ (LSCs) within the marrow, which can be identified by their distinctive profile of cell-surface markers. In an effort to identify other features of LSCs that might offer useful therapeutic targets, Ishikawa, Yoriko Saito and team performed a thorough comparative analysis between LSCs and normal blood stem cells to identify genes with functional characteristics pertinent to cancerous growth whose expression is specifically elevated in LSCs1.

Their analysis revealed two candidate cell-surface proteins, CD25 and CD32; both of these are commonly overexpressed in chemotherapy-resistant LSCs, but can also be therapeutically targeted without negatively affecting blood cell development from healthy hematopoietic stem cells, making them potentially promising targets for thwarting relapse.

In parallel, Ishikawa and colleagues have also explored methods for boosting the efficiency of chemotherapy. Standard AML drugs such as cytosine arabinoside (Ara-C) work by targeting actively dividing cells, and LSCs are believed to elude chemotherapy by entering a quiescent, non-dividing state. The researchers hypothesized that LSCs could be made more vulnerable to Ara-C via simultaneous treatment with cytokines—naturally-occurring cell signaling molecules—that stimulate them into active division2. In fact, this two-pronged treatment led to a ten-fold increase in survival rate relative to chemotherapy alone for mice that had been transplanted with human LSCs.

Previous studies have suggested that despite some risk of toxicity, cytokine treatment is relatively safe for patients, and Ishikawa’s team is actively investigating the practicality and safety of interventions based on both of their recent discoveries (Fig. 1). “We have been putting our best effort into the translation of these findings into medicine,” he says. “At the same time, we are continuing to try to identify unknown aspects of human AML and AML stem cells.”

References

  1. Saito, Y., Kitamura, H., Hijikata, A., Tomizawa-Murasawa, M., Tanaka, S., Takagi, S., Uchida, N., Suzuki, N., Sone, A., Najima, Y. et al. Identification of therapeutic targets for quiescent chemotherapy-resistant human leukemia stem cells. Science Translational Medicine 2, 17ra9 (2010).  (Link)
  2. Saito, Y., Uchida, N., Tanaka, S., Suzuki, N., Tomizawa-Murasawa, M., Sone, A., Najima, Y., Takagi, S., Aoki, Y., Wake, A. et al. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nature Biotechnology 28, 275–280 (2010). (Link)