Imperial College London
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DrNiklasFeldhahn

Faculty of Medicine, Department of Immunology and Inflammation

Senior Lecturer in Molecular Haematology
 
 
 
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Contact

 

+44 (0)20 3313 1528n.feldhahn Website

 
 
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Location

 

, 4N3DCommonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Klein:2005,
author = {Klein, F and Feldhahn, N and Mooster, JL and Sprangers, M and Hofmann, WK and Wernet, P and Wartenberg, M and Muschen, M},
journal = {J Immunol},
pages = {367--375},
title = {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 rearrangement},
url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15611260},
volume = {174},
year = {2005}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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, Ckappa and Clambda germline transcription, and rearrangement of Ig kappa L chain (IGK) and Ig lambda L chain (IGL) genes. However, STI571-treated pre-B ALL cells expressed lambda L, but almost no kappa L chains. This could be explained by STI571-induced rearrangement of the kappa-deleting element (KDE), which can delete productively rearranged Vkappa-Jkappa 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 Vkappa-Jkappa joints 6 h later and, ultimately, IGL gene rearrangement after 12 h. Consistently, up-regulation of Ckappa and Clambda 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 Jkappa- to downstream Jkappa-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.
AU  - Klein,F
AU  - Feldhahn,N
AU  - Mooster,JL
AU  - Sprangers,M
AU  - Hofmann,WK
AU  - Wernet,P
AU  - Wartenberg,M
AU  - Muschen,M
EP  - 375
PY  - 2005///
SN  - 0022-1767
SP  - 367
TI  - 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 rearrangement
T2  - J Immunol
UR  - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15611260
VL  - 174
ER  -
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