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Blood, 15 January 2005, Vol. 105, No. 2, pp. 440. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Horwitz, M. Search for Related Content PubMed Articles by Horwitz, M. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Comment on Druhan et al, page 584 G-CSF receptor mutations mix it up Marshall Horwitz UNIVERSITY OF WASHINGTON An acquired granulocyte colony-stimulating factor receptor (G-CSFR) mutation in severe congenital neutropenia (SCN) severely truncating the carboxyl terminus of the G-CSF receptor may not only explain atypical refractoriness to G-CSF treatment but upsets dogma that ligand binding initiates signal transduction by inducing subunit oligomerization. Severe congenital neutropenia (SCN), also known as Kostmann syndrome, is a genetically heterogeneous disorder most often caused by heritable mutations of the ELA2 gene encoding neutrophil elastase.1 Most patients respond to granulocyte colony-stimulating factor (G-CSF) treatment, and a subset, primarily those with ELA2 mutations,2 progress to myelodysplasia or acute myeloid leukemia. While germ-line G-CSF receptor (G-CSFR) mutations rarely cause SCN,3,4 acquired mutations of G-CSFR do commonly arise during evolution to leukemia. Because G-CSFR mutations neither invariantly herald the onset of leukemia nor accompany its emergence,5 their role in the disease is not well understood. G-CSFR mutations typically delete the carboxyl tail that is required for signaling, and thereby produce a dominant-negative effect thought to result from heterodimerization of normal and mutant chains appearing together on the cell surface. Intracellular accumulation of the 319 G-CSFR. See the complete figure in the article beginning on page 584.   Druhan and colleagues report the case of an SCN patient who acquired a chain-terminating mutation taking out the distal extracellular domain and entire transmembrane and intracellular domains of the G-CSFR. The same mutation, although apparently constitutional in origin, has previously been reported in another SCN case,3 and both patients are unresponsive to G-CSF therapy. Unexpectedly, the mutation produces a stable transcript (somehow escaping nonsense-mediated decay) whose abbreviated polypeptide heterodimerizes with normal G-CSFR subunits in the endoplasmic reticulum and/or Golgi, thus sequestering receptors before they can traffic to the cell surface. The paradigm for cytokine receptor–induced signal transduction holds that ligand binding stimulates formation of dimers or oligomers from receptor monomers, yet the implication here is that oligomers can form without ligand and a conformational change upon ligand binding instead activates signal transduction (Figure 3B of Druhan et al., "Intracellular accumulation of mutant G-CSCF Receptor." References Horwitz M, Li F-Q, Albani D, et al. Leukemia in severe congenital neutropenia: defective proteolysis suggests new pathways to malignancy and opportunities for therapy. Cancer Invest. 2003;21: 577-585. Bellanne-Chantelot C, Clauin S, Leblanc T, et al. The presence of an ELA2 mutation correlates with a more severe expression of neutropenia: study of 81 patients from the French severe chronic neutropenia register. Blood. 2003; 103: 4119-4125. Sinha S, Zhu QS, Romero G, Corey SJ. Deletional mutation of the external domain of the human granulocyte colony-stimulating factor receptor in a patient with severe chronic neutropenia refractory to granulocyte colony-stimulating factor. J Pediatr Hematol Oncol. 2003;25: 791-796.[CrossRef][Medline] [Order article via Infotrieve] Ward AC, van Aesch YM, Gits J, et al. Novel point mutation in the extracellular domain of the granulocyte colony-stimulating factor (G-CSF) receptor in a case of severe congenital neutropenia hyporesponsive to G-CSF treatment. J Exp Med. 1999;190: 497-507.[Abstract/Free Full Text] Ancliff PJ, Gale RE, Liesner R, Hann I, Linch DC. Long-term follow-up of granulocyte colony-stimulating factor receptor mutations in patients with severe congenital neutropenia: implications for leukaemogenesis and therapy. Br J Haematol. 2003;120: 685-690.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Novel mechanism of G-CSF refractoriness in patients with severe congenital neutropenia Lawrence J. Druhan, Jing Ai, Pam Massullo, Tamila Kindwall-Keller, Mark A. Ranalli, and Belinda R. Avalos Blood 2005 105: 584-591. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Horwitz, M. Search for Related Content PubMed Articles by Horwitz, M. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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