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The article focuses on the relationship between stem cell aging and the development of precancerous conditions. Topics discussed include the role of specific mutations and epigenetic changes in initiating precancerous stem cell expansion, the impact of chronic inflammation on stem cell aging, and the progression of precancer stem cells into self-renewing malignant stem cells.

A response from researcher Irving L. Weissman to several letters to the editor about his article on therapeutic cloning in the May 16, 2002 issue is presented.

The article presents the author's comments on stem cell research. According to the author, stem cells have the unique capacity to generate differentiated cells and are present in all stages of development. The inner cell mass in the blastula have some pluripotent stem cells that give rise to all types of somatic and germ-line cells.

This editorial discusses the treatment of DiGeorge syndrome and how the information gleaned from years of research on rodents can translate into effective medical treatment for this disease. The author presents a description of DiGeorge syndrome and an explanation of T-cell development. The article focuses on how the results of this research force reconsideration as to the existence or need of a thymus beyond puberty. Thymus transplantation in children can rescue children with the DiGeorge syndrome.

Background: The Hu5F9-G4 (hereafter, 5F9) antibody is a macrophage immune checkpoint inhibitor blocking CD47 that induces tumor-cell phagocytosis. 5F9 synergizes with rituximab to eliminate B-cell non-Hodgkin's lymphoma cells by enhancing macrophage-mediated antibody-dependent cellular phagocytosis. This combination was evaluated clinically.Methods: We conducted a phase 1b study involving patients with relapsed or refractory non-Hodgkin's lymphoma. Patients may have had diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma. 5F9 (at a priming dose of 1 mg per kilogram of body weight, administered intravenously, with weekly maintenance doses of 10 to 30 mg per kilogram) was given with rituximab to determine safety and efficacy and to suggest a phase 2 dose.Results: A total of 22 patients (15 with DLBCL and 7 with follicular lymphoma) were enrolled. Patients had received a median of 4 (range, 2 to 10) previous therapies, and 95% of the patients had disease that was refractory to rituximab. Adverse events were predominantly of grade 1 or 2. The most common adverse events were anemia and infusion-related reactions. Anemia (an expected on-target effect) was mitigated by the strategy of 5F9 prime and maintenance dosing. Dose-limiting side effects were rare. A selected phase 2 dose of 30 mg of 5F9 per kilogram led to an approximate 100% CD47-receptor occupancy on circulating white and red cells. A total of 50% of the patients had an objective (i.e., complete or partial) response, with 36% having a complete response. The rates of objective response and complete response were 40% and 33%, respectively, among patients with DLBCL and 71% and 43%, respectively, among those with follicular lymphoma. At a median follow-up of 6.2 months among patients with DLBCL and 8.1 months among those with follicular lymphoma, 91% of the responses were ongoing.Conclusions: The macrophage checkpoint inhibitor 5F9 combined with rituximab showed promising activity in patients with aggressive and indolent lymphoma. No clinically significant safety events were observed in this initial study. (Funded by Forty Seven and the Leukemia and Lymphoma Society; ClinicalTrials.gov number, NCT02953509 .). [ABSTRACT FROM AUTHOR]

Background: The progression of chronic myelogenous leukemia (CML) to blast crisis is supported by self-renewing leukemic stem cells. In normal mouse hematopoietic stem cells, the process of self-renewal involves the β-catenin–signaling pathway. We investigated whether leukemic stem cells in CML also use the β-catenin pathway for self-renewal. Methods: We used fluorescence-activated cell sorting to isolate hematopoietic stem cells, common myeloid progenitors, granulocyte–macrophage progenitors, and megakaryocyte–erythroid progenitors from marrow during several phases of CML and from normal marrow. BCR-ABL, β-catenin, and LEF-1 transcripts were compared by means of a quantitative reverse-transcriptase–polymerase-chain-reaction assay in normal and CML hematopoietic stem cells and granulocyte–macrophage progenitors. Confocal fluorescence microscopy and a lymphoid enhancer factor/T-cell factor reporter assay were used to detect nuclear β-catenin in these cells. In vitro replating assays were used to identify self-renewing cells as candidate leukemic stem cells, and the dependence of self-renewal on β-catenin activation was tested by lentiviral transduction of hematopoietic progenitors with axin, an inhibitor of the β-catenin pathway. Results: The granulocyte–macrophage progenitor pool from patients with CML in blast crisis and imatinib-resistant CML was expanded, expressed BCR-ABL, and had elevated levels of nuclear β-catenin as compared with the levels in progenitors from normal marrow. Unlike normal granulocyte–macrophage progenitors, CML granulocyte–macrophage progenitors formed self-renewing, replatable myeloid colonies, and in vitro self-renewal capacity was reduced by enforced expression of axin. Conclusions: Activation of β-catenin in CML granulocyte–macrophage progenitors appears to enhance the self-renewal activity and leukemic potential of these cells. N Engl J Med 2004;351:657-67. [ABSTRACT FROM AUTHOR]