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Blood, 1 September 2006, Vol. 108, No. 5, pp. 1431-1432. 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 Prchal, J. Search for Related Content PubMed Articles by Prchal, J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Comment on Garçon et al, page 1551 Erythropoietin-independent erythroid colonies: is the molecular basis clarified? Josef Prchal UNIVERSITY OF UTAH In this issue, Garçon and colleagues in Vainchenker's laboratory describe the molecular basis of erythropoietin-independent colonies (also referred to as endogenous erythroid colonies [EECs]) in polycythemia vera (PV). Garçon and colleagues provide evidence that 2 signal transduction molecules (ie, STAT5 and Bcl-xL) could explain the existence of EECs. These EECs have been useful in diagnosis of those polycythemia vera patients who do not fulfill the phenotypic criteria as outlined by either the Polycythemia Vera Study Group or the World Health Organization.1 Vainchenker's laboratory was indeed well positioned to undertake this task, since they were the first ones to focus on the role of abnormal JAK2 signaling in polycythemia vera2 and were the first to describe the JAK2 somatic mutation in polycythemia vera, JAK2V617F.3 This finding was in rapid sequence confirmed and simultaneously reported by multiple other laboratories. Since activation of JAK2 by the erythropoietin/erythropoietin receptor pathway activates multiple signal transduction mechanisms, including STAT5, MAP, PI3K, and possibly Src family kinases, the molecular mechanism of EECs remained to be determined. Garçon and colleagues report a series of experiments using inhibition of STAT5 and Bcl-xL by siRNA and overexpression of these molecules by means of retroviral transduction and conclusively demonstrate that manipulation of STAT5 and its downstream partner Bcl-xL induces the EECs. While it is pleasing to understand the molecular mechanism of EECs, it remains to be established if erythropoietin hypersensitivity and the occasional EECs observed in other primary polycythemic disorders, such as primary familiar and congenital polycythemia and Chuvash polycythemia,4 have the same EEC mechanism. These disorders are not associated with activating mutations of JAK2; does the STAT5/Bcl-L pathway also mediate them? Further, not all patients with polycythemia vera and EECs have the JAK2 mutation. In addition, in rare families inheriting the predisposition for polycythemia vera, all affected polycythemia vera patients have EECs5 but not all of them have JAK2 mutation6 (this is also our experience). The finding of Garçon and colleagues needs to be extended to other primary polycythemic states. Nevertheless, in our opinion, while the assay for EECs is not necessary for most patients presenting with elevated hematocrit and for their differential diagnosis, EECs still remain useful as a diagnostic tool for some patients as well as an important research tool. Supported by grant 1P01CA108671-O1A2 from the MPD Consortium (principal investigator, Ron Hoffman). References Prchal JF, Axelrad AA. Letter: bone-marrow responses in polycythemia vera. N Engl J Med. 1974;290: 1382.[Medline] [Order article via Infotrieve] Ugo V, Marzac C, Teyssandier I, et al. Multiple signaling pathways are involved in erythropoietin-independent differentiation of erythroid progenitors in polycythemia vera. Exp Hematol. 2004;32: 179-187.[CrossRef][Medline] [Order article via Infotrieve] James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434: 1144-1148.[CrossRef][Medline] [Order article via Infotrieve] Prchal JT. Polycythemia vera and other primary polycythemias. Curr Opin Hematol. 2005;12: 112-116.[CrossRef][Medline] [Order article via Infotrieve] Kralovics R, Stockton DW, Prchal JT. Clonal hematopoiesis in familial polycythemia vera suggests the involvement of multiple mutational events in the early pathogenesis of the disease. Blood. 2003;102: 3793-3796.[Abstract/Free Full Text] Cario H, Goerttler PS, Steimle C, Levine RL, Pahl HL. The JAK2V617F mutation is acquired secondary to the predisposing alteration in familial polycythaemia vera. Br J Haematol. 2005;130: 800-801.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Constitutive activation of STAT5 and Bcl-xL overexpression can induce endogenous erythroid colony formation in human primary cells Loïc Garçon, Christine Rivat, Chloé James, Catherine Lacout, Valérie Camara-Clayette, Valérie Ugo, Yann Lecluse, Annelise Bennaceur-Griscelli, and William Vainchenker Blood 2006 108: 1551-1554. [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 Prchal, J. Search for Related Content PubMed Articles by Prchal, J. 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