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.

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Immune reactions after RI-CBT can be categorized into three distinct subtypes.

Umbilical cord blood transplantation (CBT) is an alternative allogeneic haematopoietic stem cell transplantation (HSCT) strategy for patients with haematological diseases who do not have a matched related or unrelated donor and who need urgent transplantation. The value of CBT using myeloablative preparative regimens has already been confirmed among paediatric and adult patients (Laughlin et al, 2004;Rocha et al, 2004;Takahashi et al, 2004). However, conventional myeloablative preparative regimens are associated with significant morbidity and mortality, particularly in older patients or in those who have experienced extensive prior therapy or organ dysfunction associated with transplantation-related mortality. Various reduced-intensity preparative regimens that have been applied to such patients by several groups, including the authors of the present study, have proven feasible (Barker et al, 2003(Barker et al, , 2005Chao et al, 2004;Jacobsohn et al, 2004;Miyakoshi et al, 2004Miyakoshi et al, , 2007Yuji et al, 2005;Misawa et al, 2006;Ballen et al, 2007;Brunstein et al, 2007;Komatsu et al, 2007;Uchida et al, 2008).

Although allogeneic hematopoietic stem cell transplantation is a potentially curative approach for advanced hematologic diseases, its application to elderly people is limited because of their comorbid physical conditions and lower chance of finding suitable related donors. Umbilical cord blood transplantation with reduced-intensity pretransplant conditioning (RI-UCBT) is 1 way to avoid these obstacles. We analyzed elderly patients aged 55 years and older with hematologic diseases who underwent RI-UCBT at our institute to assess feasibility and effectiveness of this treatment approach. Among the 70 patients included, 50 died, 74% of them from nonrelapse causes. Infection was the primary cause of death. Estimated overall survival and progression-free survival at 2 years were both 23%. In multivariate analyses, standard-risk diseases, age younger than 61 years, grade 0-II acute graft-versus-host disease, and the absence of preengraftment immune reaction were significantly associated with better overall survival. RI-UCBT is a potentially curative and applicable approach for elderly patients. Higher mortality, especially from nonrelapse causes, is the biggest problem to be solved to increase the feasibility of this approach.

Bloodstream infection (BSI) is a significant problem after cord blood transplantation (CBT). However, little information has been reported on BSI after reduced-intensity CBT (RI-CBT). We retrospectively reviewed the medical records of 102 patients. The median age of the patients was 55 years (range, 17-79 years). Preparative regimens comprised fludarabine 125 to 150 mg/m 2 , melphalan 80 to 140 mg/m 2 , or busulfan 8 mg/kg and total body irradiation 2 to 8 Gy. Prophylaxis against graft-versus-host disease comprised cyclosporin or tacrolimus. BSI developed within 100 days of RI-CBT in 32 patients. The cumulative incidence of BSI was 25% at day 30 and 32% at day 100. The median onset was day 15 (range, 1-98 days). Causative organisms included Pseudomonas aeruginosa (n = 12), Staphylococcus epidermidis (n = 11), Staphylococcus aureus (n = 6), Enterococcus faecium (n = 4), Enterococcus faecalis (n = 4), Stenotrophomonas maltophilia (n = 4), and others (n = 7). Of the 32 patients with BSI, 25 (84%) died within 100 days after RI-CBT. BSI was the direct cause of death in 8 patients (25%). Univariate analysis failed to identify any significant risk factors. BSI clearly represents a significant and fatal complication after RI-CBT. Further studies are warranted to determine clinical characteristics, identify patients at high risk of BSI, and establish therapeutic strategies.

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