Citations

Abstract Macrophage inflammatory protein-1α (MIP-1α) is produced in high concentration by multiple myeloma (MM) cells in about 70% of patients, and MIP-1α levels correlate with their disease activity. Patients who have high levels of MIP-1α have a poor prognosis. Furthermore, blocking MIP-1α expression in an in vivo model of human MM profoundly decreases both tumor burden and bone destruction, suggesting that MIP-1α is an important mediator of MM bone disease. Therefore, to analyze the regulation of MIP-1α production in MM, we cloned the human MIP-1α promoter and characterized the transcription factor (TF) motifs that control MIP-1α expression in MM cells. The proximal region of MIP-1α promoter was composed of 2 sets of identical transcription regulatory regions consisting of GATA-2+ AML-1+ C/EBPα motifs. Since 2 alternatively spliced variants of the acute myeloid leukemia-1 (AML-1) class of TFs can bind the AML-1 region, AML-1A and AML-1B, the relationship between the expression levels of AML-1A or AML-1B in MM cells and their capacity to express MIP-1α was examined. AML-1A mRNA was relatively overexpressed compared with AML-1B in MM cell lines that produced high levels of MIP-1α (> 1 ng/mL per 106 cells per 72 hours), but AML-1A was not increased in MM cell lines that expressed less than 200 pg/mL MIP-1α. More importantly, the ratio of AML-1A to AML-1B mRNA levels was also increased in 3 of 3 highly purified myeloma cells from patients with MM who expressed increased amounts of MIP-1α. The ratio of AML-1A to AML-1B mRNA in patients with MM was 8-fold higher than in healthy controls. Transduction of AML-1B into the MM-derived MM.1S and ARH-77 cells totally blocked MIP-1α production, while AML-1A did not further increase the already high levels of MIP-1α produced by these cells. Taken together, these data demonstrate that in patients with MM who produce increased concentrations of MIP-1α, the relative level of AML-1B is significantly decreased compared with healthy controls. The data suggest that strategies that enhance AML-1B expression or decrease AML-1A in MM cells may be beneficial therapeutically.

AbstractCurrent therapeutic options for myeloid metaplasia with myelofibrosis (MMM) are limited. A pilot study was conducted of autologous peripheral blood stem cell (PBSC) collection in 27, followed by transplantation in 21 patients with MMM. The median age was 59 (range 45-75) years. PBSCs were mobilized at steady state (n = 2), after granulocyte colony-stimulating factor (G-CSF) alone (n = 17), or after anthracycline-cytarabine induction plus G-CSF (n = 8). A median of 11.6 × 106 (range 0 to 410 × 106) CD34+ cells per kilogram were collected. Twenty-one patients then underwent myeloablation with oral busulfan (16 mg/kg) and PBSC transplantation. The median times to neutrophil and platelet recovery after transplantation were 21 (range 10-96) and 21 (range, 13 to ≥ 246) days, respectively. Five patients received back-up PBSC infusion because of delayed neutrophil or platelet recovery. The median follow-up is 390 (range 70-1623) days after transplantation, and the 2-year actuarial survival is 61%. After transplantion, 6 patients died: 3 of nonrelapse causes (1 within 100 days of PBSC infusion) and 3 of disease progression. Erythroid response (hemoglobin ≥ 100 g/L [10 gm/dL] without transfusion for ≥ 8 weeks) occurred in 10 of 17 anemic patients. Four of 8 patients with a platelet count less than 100 × 109/L (100 000/μL) responded with a durable platelet count more than 100 × 109/L (100 000/μL). Symptomatic splenomegaly improved in 7 of 10 patients. It is concluded that (1) PBSC collection was feasible and stable engraftment occurred after transplantation in most patients with MMM, (2) myeloablation with busulfan was associated with acceptable toxicity, (3) a significant proportion of patients derived clinical benefit after treatment, and (4) further investigation of this novel approach is warranted.