SCIENCE@home

Identification of Therapeutic Targets for Quiescent, Chemotherapy-Resistant Human Leukemia Stem Cells

Yoriko Saito,H. Kitamura,A. Hijikata,Mariko Tomizawa-Murasawa,Satoshi Tanaka,S. Takagi,N. Uchida,Nahoko Suzuki,Akiko Sone,Y. Najima,Hidetoshi Ozawa,A. Wake,S. Taniguchi,L. Shultz,O. Ohara,F. Ishikawa

Published 2010 in Science Translational Medicine

ABSTRACT

CD32 and CD25, molecules specifically found in human leukemia stem cells, are promising targets for therapy. In the blood cancer acute myelogenous leukemia (AML), red blood cell precursors in the bone marrow cells divide extremely rapidly, releasing large numbers of immature cells into the bloodstream. AML can generally be treated, but many patients suffer from relapse, likely a result of pockets of residual, diseased stem cells that resist the initial treatment. To devise tools to selectively kill these cancer-initiating cells, Saito et al. have identified molecules that are unique to these cells, finding two promising surface proteins—CD32 and CD25, the alpha chain of the IL-2 receptor. To identify these markers, the authors used two microarray platforms to screen for mRNAs present in the rare leukemia stem cells but not in healthy human blood cell–generating stem cells. It was important not to choose molecules also present in normal cells to avoid potential damaging side effects by any ultimately developed therapeutic agent that targets the molecule. The two platforms yielded 217 and 75 genes, from which the authors selected genes for cell surface or extracellular proteins plus cell signaling and known regulatory proteins. They then validated the differential expression of these proteins in leukemic cells with more stringent methods, ultimately settling on 25 final candidates. In 61 samples of cells from patients with leukemia, the authors found that two of their candidate molecules, CD32 and CD25, were more frequently expressed in the leukemia stem cells than others and, in over half of the samples, there were large amounts of both of these molecules. Two additional features of CD32 and CD25 recommended these particular molecules as good targets for therapy: They remain on the leukemia stem cells, even after treatment with cytarabine, a common chemotherapy drug. And their inhibition does not interfere with normal blood cell development. The final word on the utility of these molecules as drug targets awaits further experimentation, but the stage is set for a promising test. Human acute myeloid leukemia (AML) originates from rare leukemia stem cells (LSCs). Because these chemotherapy-resistant LSCs are thought to underlie disease relapse, effective therapeutic strategies specifically targeting these cells may be beneficial. Here, we report identification of a primary human LSC gene signature and functional characterization of human LSC-specific molecules in vivo in a mouse xenotransplantation model. In 32 of 61 (53%) patients with AML, either CD32 or CD25 or both were highly expressed in LSCs. CD32- or CD25-positive LSCs could initiate AML and were cell cycle–quiescent and chemotherapy-resistant in vivo. Normal human hematopoietic stem cells depleted of CD32- and CD25-positive cells maintained long-term multilineage hematopoietic reconstitution capacity in vivo, indicating the potential safety of treatments targeting these molecules. In addition to CD32 and CD25, quiescent LSCs within the bone marrow niche also expressed the transcription factor WT1 and the kinase HCK. These molecules are also promising targets for LSC-specific therapy.

PUBLICATION RECORD

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-56 of 56 references · Page 1 of 1

CITED BY

Showing 1-100 of 462 citing papers · Page 1 of 5

12345
Next