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Bringing blood to life Since ancient times, the heart and blood have been inextricably linked as fundamental elements to the process of life. William Harvey was the first to provide a plausible mechanism for blood circulation when in 1628 he defined the circulatory system to comprise a cardiac pump, intact vascular system, and recirculating blood. Harvey believed that blood was the fountain of life, the first (tissue) to live, and the last to die. His thesis has been supported in part by modern evidence that murine embryos mutant for genes necessary for blood, endothelial, and/or cardiac development who fail to establish or maintain circulation perish in utero. Harvey never articulated when he believed the blood comes to “life” (circulation commences) during mammalian development. Emergence of primitive erythroblasts (PEs) and nascent endothelial cells on embryonic day (E) 7.0 in the murine yolk sac may herald the beginnings of a circulatory system. But beating of the developing heart tube and linkage of the yolk sac and embryonic vascular systems on E8.25 is identified by some as evidence for the onset of systemic blood flow. But is blood flow equivalent to circulation? When does circulation (as defined by Harvey) begin in the murine embryo? McGrath and colleagues (page 1669) provide compelling evidence that circulation is established in a graded series of maturational steps. Using simple tools and clever intuition, they examined murine embryos from E8.0 to E10.5 to determine the steady state density of PEs in the embryo proper and the distribution of PEs in the developing embryonic vessels. They report that the first PEs enter embryonic vessels at the 4 somite pair (sp) stage of development (E8.25) but that complete equilibration of PEs in the circulation is not accomplished until 35 sp (E10.5). What takes so long? The authors suggest that the process of cardiac maturation and/or vascular BLOOD, 1 MARCH 2003 䡠 VOLUME 101, NUMBER 5 remodeling may regulate the dispersal of PEs throughout the vasculature. William Harvey would be intrigued. —Mervin C. Yoder Jr Indiana University School of Medicine Extending the scope of FTIs Advances in molecular biology and the understanding of signal transduction are allowing us to identify novel targets for the development of drugs for hematologic malignancies. One such potential target is farnesyl transferase, the enzyme responsible for the prenylation of proteins. Prenylation, the addition of a 15-carbon unsaturated polymer derived from the lipid pathway (a farnesyl group) appears to be important in posttranslational modification of several proteins critical to cell signaling, proliferation, and differentiation. Farnesyl transferase inhibitors (FTIs) have been developed to obstruct this process. FTIs have demonstrated anticancer activity as single agents and in combination with standard cytotoxic chemotherapy in solid tumors. In the first clinical trial of an FTI in the hematologic malignancies, Karp et al (Blood. 2001;97:3361-3369) demonstrated both efficacy and tolerability of FTI R115777 (Zarnestra) in patients with acute leukemias. In this issue Cortes and colleagues (page 1692) report their encouraging results of a clinical trial of this agent in patients with a variety of hematologic malignancies: CML, myelofibrosis, and multiple myeloma. Patients were treated at a dose of 600 mg orally twice a day for 4 weeks every 6 weeks. Responses were seen in 7 of 22 patients with CML, 4 of 8 patients with myelofibrosis, and only 1 of 10 patients with myeloma. This dosing schedule required dose interruptions and/or reductions in 58% of the patients. Alternate schedules or doses might further enhance the efficacy, by allowing prolonged administration if toxicity is decreased. The authors also report their correlation of response with baseline VEGF levels, as well as with changes in VEGF concentrations with therapy, a finding that they wish to pursue in further studies. Despite uncertainty about the true target of FTIs, this agent has promising activity in a variety of hematologic malignancies, and further studies are warranted. —Selina M. Luger University of Pennsylvania Cancer Center Closing the gap for detection of residual posttransplantation leukemia? The detection of minimal residual disease (MRD) after allogeneic hematopoietic stem cell transplantation (HSCT) by molecular methods has become an important diagnostic tool for clinical decision-making with regard to posttransplantation immunomodulatory measures, such as the withdrawal of immunosuppression or adoptive infusions of donor lymphocytes. The high efficacy of early interventions directed against residual molecular and cytogenetic disease after allogeneic HSCT is best documented for imminent relapses of chronic myelogenous leukemia as demonstrated by the induction of complete and durable cytogenetic, as well as molecular, responses in patients with residual cells bearing the bcr-abl gene rearrangement and its chimeric transcripts. Indeed, the success of adoptive cellular immunotherapy of MRD after allogeneic HSCT currently represents some of the most convincing clinical evidence supporting the concept of cellular immunotherapy of human cancer. The Wilms tumor suppressor gene (WT1) encodes a zinc-finger transcriptional factor that can modulate the expression of several genes coding for growth factors and their 1665