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Tracing the Pre-B to Immature B Cell Transition in Human Leukemia Cells Reveals a Coordinated Sequence of Primary and Secondary IGK Gene Rearrangement, IGK Deletion, and IGL Gene Rearrangement¹

Florian Klein^*, Niklas Feldhahn^*, Jana L. Mooster^*, Mieke Sprangers^*, Wolf-Karsten Hofmann, Peter Wernet^*, Maria Wartenberg and Markus Müschen^2,*

^* Laboratory for Molecular Stem Cell Biology, Center for Biomedical Research and Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany; Institute for Neurophysiology, University of Cologne, Cologne, Germany; and Department of Hematology and Oncology, University Hospital, Frankfurt/Main, Germany

The BCR-ABL1 kinase expressed in acute lymphoblastic leukemia (ALL) drives malignant transformation of pre-B cells and prevents further development. We studied whether inhibition of BCR-ABL1 kinase activity using STI571 can relieve this differentiation block. STI571 treatment of leukemia patients induced expression of the Ig L chain-associated transcription factors IRF4 and SPIB, up-regulation of RAG1 and RAG2, C and C germline transcription, and rearrangement of Ig L chain (IGK) and Ig L chain (IGL) genes. However, STI571-treated pre-B ALL cells expressed L, but almost no L chains. This could be explained by STI571-induced rearrangement of the -deleting element (KDE), which can delete productively rearranged V-J joints. Amplifying double-strand breaks at recombination signal sequences within the IGK, KDE, and IGL loci revealed a coordinated sequence of rearrangement events induced by STI571: recombination of IGK gene segments was already initiated within 1 h after STI571 treatment, followed by KDE-mediated deletion of V-J joints 6 h later and, ultimately, IGL gene rearrangement after 12 h. Consistently, up-regulation of C and C germline transcripts, indicating opening of IGK and IGL loci, was detected after 1 and 6 h for IGK and IGL, respectively. Continued activity of the recombination machinery induced secondary IGK gene rearrangements, which shifted preferential usage of upstream located J- to downstream J-gene segments. Thus, inhibition of BCR-ABL1 in pre-B ALL cells 1) recapitulates early B cell development, 2) directly shows that IGK, KDE, and IGL genes are rearranged in sequential order, and 3) provides a model for Ig L chain gene regulation in the human.

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