Deregulation of insulin-like growth factor-1 receptor (IGF-1R) is closely associated with malignant transformation and tumor cell survival in various cancers. We found that IGF-1R expression level in leukemia cells positively correlated with the percentage of blast in bone marrow from de novo acute myeloid leukemia (AML) patients. Moreover, we showed that NVP-ADW742, a novel small weight molecular inhibitor of IGF-IR, could induce apoptosis in both HL-60 cell line and primary AML blasts. However, no significant alteration of cell cycle was observed in HL-60 cells. Further studies revealed that NVP-ADW742 induced Akt dephosphorylation, which might subsequently induce p38 phosphorylation and decrease antiapoptotic protein Bcl-2 expression in HL-60 cells. Finally, we demonstrated that NVP-ADW742 could synergize with Ara-C to induce the kill in a subset of drug-resistant AML specimens. We suggested that IGF-lR targeting might be therapeutically beneficial for some AML patients.

Multiple myeloma (MM) is a malignancy of differen-Multiple myeloma (MM) is the prototypic monoclonal Bcell neoplasm that is derived from the autonomous proliferation of plasma cells and associated with paraprotein production and osteolytic bone lesions. MM primarily affects middle-aged to elderly patients. Blacks and males are affected more often than whites and females. 1 MM has remained an incurable disease, and effective therapeutic approaches are urgently required for patients with MM at different risk groups. Standard prognostic factors include serum ␤ 2 -microglobulin, C-reactive protein, bone marrow plasma cell morphology, and plasma cell proliferation (plasma cell labeling index). 1-3 These factors are independently associated with prognosis of patients with MM. Recently, there is considerable interest in characterizing genomic markers to establish prognostic models that allow a better estimation of an individual patient's prognosis.Chromosomal abnormalities are among the most important prognostic parameters for patients with MM. Of particular note, deletions of 13q remain independent adverse prognostic factors. 4 -6 However, conventional karyotyping has been hampered by the slow growth of MM cells in cell cultures, and chromosomal abnormalities are often missed by this technique. Of the cases studied, 50 to 70% showed normal karyotypes originating from the myeloid elements. 7-11 Therefore, cell-targeting methods are essential for the analysis of genomic aberrations in MM.Fluorescent in situ hybridization (FISH) allows detection of chromosomal aberrations in both actively dividing cells and interphase nuclei. Recently, the cytoplasm immunoglobulin (Ig) enhanced interphase FISH has been used to detect the most common genomic abnormalities in 351 patients with MM, including deletions of 13q14 and 17p13.1 and 14q32 translocations [t(4,14)(p16;q32), t(14;16)(q32;q23), and t(11;14)(q13;q32)]. 12 Genomic aberrations have been detected in 54.2% of the tested population for 13q14 deletions, 33.1% for 14q32 translocations, and 10.7% for the 17p13.1 deletion. 12 Importantly, three distinct prognostic groups have been identified, including those with a median survival time of 24.7 months [the t(4;14) and/or t(14;16), and/or 17p13.1 deletion], 42.3 months [13q14 deletions without the t(4;14), t(14;16), or 17p13.1 deletion], and 50.5 months [only the

In utero transplantation of xenogeneic stem cells into animals (such as mouse, sheep, goats) is a new approach to the studies of the engraftmen, expansion and development of foreign cells in vivo. In addition, such an approach is able to offer a model to clinical potential for correcting or replacing damaged tissues in a variety of disorders, including many that are inherent as well as acquired. Recently, we generated a human/goat hematopoietic stem cell (HSC) xenogeneic model to investigate the engraftment, expansion and development of human hematopoietic cells at an in vivo level. Human HSCs (lin-cells) were isolated and purified from fresh cord blood, and then injected intraperitoneally into pre-immune fetal goats at 55–65 gestation days (term: 145 days). A total of 50 fetal goats were injected. The growth and development of the recipient goats were monitored by B-type ultrasound scan. Ten goats suffered miscarriage due to GVH response; 39 recipients survived a complete gestation and were born alive. All these live-born goats were healthy and grew very well. They could produce offspring normally. In order to determine whether human cells were present longterm in the circulatory blood of the recipient goats, FACS, real-time PCR, RT-PCR, and Southern-blot hybridization as well as FISH were used to analyze the genotype and phenotype up to 11 months after birth. The results showed that hematopoietic chimerism (on average, >108 human cells per goat) was documented in 90% (35/39) of live-born goats that had been originally transplanted with 105 human HSCs. The regenerated human cells included myeloid, B-lymphoid and erythroid lineages as well as more primitive cells as shown by specific positive staining for human CD14, CD20, glycophorin A (GPA) and CD34, and the detection of human-specific DNA sequences and human GPA and CD34 transcripts in the blood of the transplanted goats. No human T or NK-lineage cells were detected. These studies demonstrate the feasibility of using in utero-transplanted fetal goats as a new approach for evaluating the longterm engraftment potential, expansion and development of human hematopoietic cells in vivo.