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Blood, 1 January 2007, Vol. 109, No. 1, pp. 7-8. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Emanuel, P. D. Search for Related Content PubMed Articles by Emanuel, P. D. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Comment on Germeshausen et al, page 93 Drifting precariously due to lost tyrosines Peter D. Emanuel UNIVERSITY OF ALABAMA AT BIRMINGHAM While likely being neither a necessary nor a sufficient factor, Germeshausen and colleagues demonstrate that 78% of patients with severe congenital neutropenia who undergo a malignant transformation to leukemia harbor mutations in the G-CSF receptor gene, CSF3R. Treatment with pharmacologic doses of recombinant granulocyte colony-stimulating factor (G-CSF) has dramatically changed the clinical course of patients with severe congenital neutropenia. With more than 95% of patients responding to G-CSF, infection rates have fallen, mortality has been reduced, and quality of life has increased. The increased life expectancy in severe congenital neutropenia has unearthed a new problem, an approximate 15% risk for transformation to myelodysplasia or leukemia.1 Initial fears that the G-CSF treatment itself caused the problem have been dispelled. It is now becoming more clear that as patients with severe congenital neutropenia (CN) live longer, somatic mutations are acquired in their hematopoietic cells that are associated with the progression to a malignant leukemia phenotype. The neutrophil elastase gene, ELA2, has been demonstrated to be the causative defect in cyclic neutropenia,2 presumably by mutated ELA2 causing impaired proliferation and accelerated apoptosis in myeloid progenitor cells. Similarly, heterozygous ELA2 mutations have been found in 60% of patients with CN, indicating that it is likely a cooperating molecular event in CN pathogenesis. The earliest reports of another somatic event, CSF3R mutations in patients with CN that had transformed to leukemia, began to appear in the literature more than a decade ago.3,4 Prior to the report by Germeshausen and colleagues in this issue of Blood, 8 different mutations had been described in the cytoplasmic carboxyterminal–negative regulatory domain. The present report importantly describes 10 new mutations. This report of an extensive cohort of patients with a lengthy longitudinal analysis contains data on 148 patients with CN, 23 of whom developed secondary monosomy 7, myelodysplasia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or chronic myelomonocytic leukemia (CMML). Of the cohort of 148 patients with CN, 61 (41%) were found to harbor CSF3R mutations, including 5 of 30 patients with CN who never received G-CSF therapy, adding further evidence that G-CSF therapy does not cause these mutations. Since only 23 in the cohort developed subsequent transformation, and not 61, this proves that CSF3R mutations are not sufficient for malignant transformation. Most (18 [78%]) of the 23 patients with CN who had secondary transformation had CSF3R mutations in their hematopoietic cells, also proving that this is not a necessary condition for transformation. Important sequence analysis in this study demonstrated that all of the CSF3R mutations in all patients led to loss of at least 1 intracytoplasmic tyrosine residue (Y764), but in many cases, 2, 3, or sometimes all 4 critical tyrosine residues on the G-CSF receptor were lost in the nonsense mutations (see figure). These 4 tyrosine residues are vital docking sites for intracytoplasmic SH2-containing signaling molecules necessary for the transmission ofregulatory signals for the proliferation, differentiation, and survival properties of myeloid progenitor cells.5,6 Without these critical tyrosine residues serving as docking sites, these intracytoplasmic SH2-containing signaling molecules are left to precariously drift in the cytoplasmic sea, unable to exert their normal regulatory control. View larger version (33K): [in this window] [in a new window]   Schematic representation of the G-CSF receptor with extracellular, transmembrane, and cytoplasmic regions as indicated. Gray-hatched boxes represent conserved cytoplasmic subdomains. Four cytoplasmic tyrosine residues indicated in red.   Therefore, while CSF3R mutations are neither necessary nor sufficient for secondary transformation, they are, at the very least, a highly predictive marker that patients with CN who have CSF3R mutations need to be kept under close observation. But the more likely scenario is that CSF3R mutations in fact contribute at some stage, along with other cooperating molecular events that lead to leukemogenesis. Footnotes The author declares no competing financial interests. References Freedman MH, Bonilla MA, Fier C, et al. Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy. Blood 2000; 96:429–436.[Abstract/Free Full Text] Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC. Mutations in ELA2 encoding neutrophil elastase define a 21-day biological clock in cyclic haematopoiesis. Nat Genet 1999; 23:433–436.[CrossRef][Medline] [Order article via Infotrieve] Dong F, Hoefsloot LH, Schelen AM, et al. Identification of a nonsense mutation in the granulocyte-colony-stimulating factor receptor in severe congenital neutropenia. Proc Natl Acad Sci U S A 1994; 91:4480–4484.[Abstract/Free Full Text] Dong F, Brynes RK, Tidow N, Welte K, Lowenberg B, Touw IP. Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia. N Engl J Med 1995; 333:487–493.[Abstract/Free Full Text] Akbarzadeh S, Ward AC, McPhee DO, Alexander WS, Lieschke GJ, Layton JE. Tyrosine residues of the granulocyte colony-stimulating factor receptor transmit proliferation and differentiation signals in murine bone marrow cells. Blood 2002; 99:879–887.[Abstract/Free Full Text] Hermans MH, van de Geijin GJ, Antonissen C, et al. Signaling mechanisms coupled to tyrosines in the granulocyte colony-stimulating factor receptor orchestrate G-CSF-induced expansion of myeloid progenitor cells. Blood 2003; 101:2584–2590.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: results of a long-term survey Manuela Germeshausen, Matthias Ballmaier, and Karl Welte Blood 2007 109: 93-99. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Emanuel, P. D. Search for Related Content PubMed Articles by Emanuel, P. D. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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