1. ¹Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
2. ²Peking University Institute of Hematology, Peking University People's Hospital, Beijing, China
3. ³Research Unit for Human Disease Models, RIKEN Research Center for Allergy and Immunology (RCAI), Yokohama, Japan
4. ⁴Department of Pediatrics, Kyushu National Cancer Center, Fukuoka, Japan
5. ⁵The Jackson Laboratory, Bar Harbor, Maine, USA

Correspondence: Dr F Ishikawa, Research Unit for Human Disease Models, RIKEN Research Center for Allergy and Immunology (RCAI), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. E-mail: f_ ishika@rcai.riken.jp

Received 1 October 2007; Revised 12 February 2008; Accepted 10 March 2008; Published online 17 April 2008.

Abstract

The presence of rare malignant stem cells supplying a hierarchy of malignant cells has recently been reported. In human acute myelogenous leukemia (AML), the leukemia stem cells (LSCs) have been phenotypically restricted within the CD34+CD38- fraction. To understand the origin of malignant cells in primary human B-precursor acute lymphocytic leukemia (B-ALL), we established a novel in vivo xenotransplantation model. Purified CD34+CD38+CD19+, CD34+CD38- CD19+ and CD34+CD38- CD19- bone marrow (BM) or peripheral blood (PB) cells from three pediatric B-ALL patients were intravenously injected into sublethally irradiated newborn NOD/SCID/IL2r^null mice. We found that both CD34+CD38+CD19+ and CD34+CD38- CD19+ cells initiate B-ALL in primary recipients, whereas the recipients of CD34+CD38- CD10- CD19- cells showed normal human hematopoietic repopulation. The extent of leukemic infiltration into the spleen, liver and kidney was similar between the recipients transplanted with CD34+CD38+CD19+ cells and those transplanted with CD34+CD38- CD19+ cells. In each of the three cases studied, transplantation of CD34+CD38+CD19+ cells resulted in the development of B-ALL in secondary recipients, demonstrating self-renewal capacity. The identification of CD34+CD38+CD19+ self-renewing B-ALL cells proposes a hierarchy of leukemia-initiating cells (LICs) distinct from that of AML. Recapitulation of patient B-ALL in NOD/SCID/IL2r^null recipients provides a powerful tool for directly studying leukemogenesis and for developing therapeutic strategies.