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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1894-1903. Prepublished online as a Blood First Edition Paper on June 24, 2008; DOI 10.1182/blood-2008-01-129221. This Article Full Text (PDF) All Versions of this Article: blood-2008-01-129221v1 112/5/1894    most recent 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 Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Taylor, B. J Articles by Pilarski, L. M Search for Related Content PubMed PubMed Citation Articles by Taylor, B. J Articles by Pilarski, L. M Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 2, 2008 Accepted June 6, 2008 Analysis of clonotypic switch junctions reveals multiple myeloma originates from a single class switch event and exhibits ongoing mutation in the isotype switched progeny Brian J Taylor, Jitra Kriangkum, Julie A Pittman, Michael J Mant, Tony Reiman, Andrew R Belch, and Linda M Pilarski* Oncology, University of Alberta, Edmonton, Alberta, Canada Medicine, University of Alberta, Edmonton, Alberta, Canada * Corresponding author; email: lpilarsk{at}ualberta.ca. Multiple myeloma (MM) is a cancer of plasma cells (PC) expressing immunoglobulin heavy chain (IgH) post-switch isotypes. The discovery of earlier stage cells related to post-switch PC, called pre-switch clonotypic IgM (cIgM) cells led to the hypothesis that cIgM cells may be MM progenitors, replenishing the tumor throughout malignancy. We speculated that cIgM cells do this by undergoing class switch recombination (CSR), a process detectable in post-switch PC as multiple IgH switch junctions associated with a single clonotypic IgH V/D/J. We addressed this with a specific clonotypic-switch PCR, informative for 32/41 cases. Here we made two significant discoveries: (1) in all cases we detected only a single clonotypic switch fragment that persists over time (1-7.6 years), confirmed by switch junction sequencing, and (2) we detected ongoing mutation upstream of the switch junction in 5/6 patients, often targeting the intronic enhancer, a key control region in IgH expression. The presence of a single, unchanging clonotypic switch junction suggests that cIgM cells are not MM-PC progenitors; rather, post-switch PC arise from a single cIgM cell, and MM-PC progenitors reside in the post-switch population. Furthermore, mutations revealed here provide a new marker to identify MM-PC progenitors and aggressive clones that evolve throughout malignancy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. A. Burger, P. Ghia, A. Rosenwald, and F. Caligaris-Cappio The microenvironment in mature B-cell malignancies: a target for new treatment strategies Blood, October 15, 2009; 114(16): 3367 - 3375. [Abstract] [Full Text] [PDF]

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