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Blood, 15 November 2005, Vol. 106, No. 10, pp. 3338-3339. 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 Lieto, L. D. Articles by Coligan, J. E. Search for Related Content PubMed Articles by Lieto, L. D. Articles by Coligan, J. E. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Comment on Lin et al, page 3567 CD94 1A/1B: a window opens into NK-cell development Louis D. Lieto, Francisco Borrego, and John E. Coligan NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES Lin and colleagues report that patients with lymphoblastic lymphomas (LBLs) expressing CD94 1A transcripts had a better prognosis than patients with LBLs lacking CD94 1A transcript expression. CD94 gene expression is regulated by distal and proximal promoters that transcribe unique initial exons specific to each promoter.1,2 These exons do not affect the coding sequence of the CD94 protein. The proximal promoter (CD94 1B transcript) is constitutively active; while the distal promoter (CD94 1A transcript) is induced only after activation with interleukin 2 (IL-2) and/or interleukin 15 (IL-15).1 In this issue of Blood, Lin and colleagues show that CD94 transcript expression can be used to distinguish lymphoblastic lymphomas (LBLs) as having been derived from immature natural killer (NK) versus T cells, and that differential CD94 transcript expression may characterize early NK-cell development. The majority of the human natural killer (NK) cells develops from hematopoietic stem cells (HSCs) in the adult bone marrow, but a fraction also descends from lymph node HSCs and from early precursors in the thymus. In the currently accepted paradigm of NK-cell ontogeny, there is a first phase, in which HSCs require stem-cell factor (SCF) and Flt3 ligand to commit to the NK-cell lineage, followed by a second phase, in which the NK progenitors under the influence of cytokines, principally IL-15, differentiate and mature into functional NK cells.3 In addition, several transcription factors, including members of the zinc finger, external transcribed spacer (ETS), and interferon regulatory factor families, are also involved, at different stages, in the development and generation of mature NK cells. Major histocompatibility complex (MHC) class I–specific receptors appear during the final steps of NK-cell maturation. Of these receptors, CD94/NKG2 receptors that recognize histocompatibility leukocyte antigen E (HLA-E) are expressed earlier and at a greater frequency than killer immunoglobulin-like receptors (KIRs).4 Virtually all human NK cells express CD94. In recent years, significant progress has been made in the elucidation of the mechanisms controlling transcription of the CD94 gene.1,2 The work of Lin and colleagues sheds some light on the use of the two different CD94 promoters, if not why the regulation of the CD94 gene requires two promoters. The authors demonstrated that expression of the CD94 1A transcripts characterized thymic NK precursors that express the chain of the IL-15 receptor (IL-15R), while in peripheral tissues CD94 1B transcripts are more prevalent. This pattern of expression indicates that the regulation of CD94 expression is developmental stage specific (Figure 1), perhaps involving different sets of transcription factors or complexes. View larger version (75K): [in this window] [in a new window]   A 3-stage model of NK development. The cytoplasmic CD3+ nuclear TdT+ bipotent T/NK-cell precursor may develop into either immature T cells under the actions of E2A and IL-2 or immature NK cells under the actions of ID2 and IL-15. Lineage commitment is fully established when immature NK cells express CD94 1A transcripts. The model shows the expression of the CD94 receptor on immature NK cells, but it is unclear whether it is expressed on the surface at this stage of development. Illustration by Paulette Dennis.   The investigators studied the expression of CD94 1A and 1B transcripts in extranodal nasal-type NK/T-cell lymphoma (ENNLs) and LBLs from lymph nodes and mediastinal biopsies in order to determine if CD94 transcript expression was NK LBL specific. T-cell markers (intracytoplasmic CD3 and terminal deoxynucleotidyl transferase [TdT]) or NK markers (CD161 and KIR) can be expressed in LBLs from both lineages. Lin and colleagues were able to distinguish two groups of LBLs: one group that expressed CD94 1A and was classified as originating from immature NK cells, and a second group that was CD94 1A– and predominately of T-cell origin. Though classification of LBLs into NK- and T-cell origin based on the expression of CD94 1A is not perfect because of the possibility of CD94 1A (and 1B) expression by T cells, the expression of CD94 1A appears to have important clinical consequences. Remarkably, patients with CD94 1A+ LBLs had a 100% survival rate at 2 years versus 27% for patients who were CD94 1A–. These results provide valuable refinement of the LBL classification and raise the question as to whether CD94 1A expression has direct bearing on LBL disease progression. Future studies by Lin et al's laboratory and other groups should help explain what mechanisms, transcription factors, and/or environmental factors are involved in the switch from one CD94 promoter to the other. Better models of NK-cell development have to be established to understand CD94 gene transcription and conclusively assign CD94 1A transcripts to immature NK cells and CD941B transcripts to more mature NK cells. References Lieto LD, Borrego F, You CH, Coligan JE. Human CD94 gene expression: dual promoters differing in responsiveness to IL-2 or IL-15. J Immunol. 2003;171: 5277-5286.[Abstract/Free Full Text] Wilhelm BT, Landry JR, Takei F, Mager DL. Transcriptional control of murine CD94 gene: differential usage of dual promoters by lymphoid cell types. J Immunol. 2003;171: 4219-4226.[Abstract/Free Full Text] Vosshenrich CA, Samson-Villeger SI, Di Santo JP. Distinguishing features of developing natural killer cells. Curr Opin Immunol. 2005;17: 151-158.[CrossRef][Medline] [Order article via Infotrieve] Colucci F, Caligiuri MA, Di Santo JP. What does it take to make a natural killer? Nat Rev Immunol. 2003;3: 413-425.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: CD94 1A transcripts characterize lymphoblastic lymphoma/leukemia of immature natural killer cell origin with distinct clinical features Chung-Wu Lin, Ting-Yun Liu, Shee-Uan Chen, Kun-Teng Wang, L. Jeffrey Medeiros, and Su-Ming Hsu Blood 2005 106: 3567-3574. [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 Lieto, L. D. Articles by Coligan, J. E. Search for Related Content PubMed Articles by Lieto, L. D. Articles by Coligan, J. E. 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