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Blood, 15 January 2008, Vol. 111, No. 2, pp. 477.
Taking ALPS down a NotchNATIONAL INSTITUTES OF HEALTH
Notch activation is an early and critical event during T-cell leukemogenesis, hence Notch signal inhibition is a desirable and feasible intervention to abrogate the process of lymphocyte accumulation and antibody production secondary to apoptosis defects as shown in 2 murine models here. However, prudent and diligent assessment of the risks and benefits of any such therapies should be imperative, especially in many nonmalignant lymphoproliferative and autoimmune disorders, including autoimmune lymphoproliferative syndrome (ALPS).
Historically, studies in Fas-deficient MRL/lpr–/– mice, which develop massive lymphadenopathy, hepatosplenomegaly, autoimmune nephropathy, and expansion of double-negative (DN) T lymphocytes, have provided insights into the seminal role of Fas and apoptosis in lymphocyte homeostasis and the pathophysiology of a similar syndrome in humans.2 Subsequently named autoimmune lymphoproliferative syndrome (ALPS), this disorder is most often associated with heterozygous mutations in the gene encoding the Fas protein inherited as an autosomal dominant trait with variable penetrance. ALPS has a distinct clinical phenotype. This results from an accumulation of lymphocytes due to impaired apoptosis and leads to childhood onset chronic lymphadenopathy, hepatosplenomegaly, multilineage cytopenias secondary to sequestration and autoimmune destruction, and an increased risk of B-cell lymphoma. While the vast majority of the approximately 400 ALPS patients studied worldwide over the past 15 years have a self-limiting course, a subset have severe disease and require treatment for cytopenias. They often respond to conventional immunosuppressive regimens consisting of corticosteroids and/or alternative steroid-sparing medications.3
Teachey et al show that inhibition of the
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
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| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
-secretase inhibitor (GSI) on an extended use schedule of 5mg/kg/day over 6 to12 weeks in 2 strains of Fas-deficient (CBA/lpr–/– and MRL/lpr –/–) murine models of lymphoproliferation and autoimmune disease. First described in 1917 by Thomas Hunt Morgan (for whom the centimorgan unit of measure of genetic linkage is named), the notched-wing phenotype of Drosophila melanogaster with thickening of the wing vein is a sex-linked recessive loss-of-function mutation. It is associated with the evolutionarily conserved eponymous protein Notch that plays a pleiotropic role during cellular ontogeny and epigenetic silencing by regulating angiogenesis, myogenesis, neurogenesis, and gliogenesis. Recent studies have elucidated the role of Notch transcriptional networks as germane to T-cell development, activation, and differentiation signaling.
β + /CD4-/CD8-) T lymphocytes comprising 21% (9985 cells) of the peripheral blood mononuclear cells in a patient with profound lymphoproliferation due to ALPS. (Flow cytometry figure courtesy of Margaret Brown, NIH)