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A second NOTCH1 chromosome rearrangement: t(9;14)(q34.3;q11.2) in T-cell neoplasia

Leukemia volume 23, pages 1003–1006 (2009)Cite this article

Cytogenetic analysis revealed t(9;14)(q34.3;q11.2) in both HD-MAR and HT-1 cells, with NOTCH1 breakpoints inside fosmid 80019F4 accompanied in HD-MAR cells by deletion of ∼80 kbp corresponding to NEC (Figures 1a–d). Fluorescence in situ hybridization (FISH) also showed 14q11.2 breakpoints in both HD-MAR and HT-1 cells within the TRAV locus. These observations define an hitherto unlisted rearrangement (http://atlasgeneticsoncology.org//index.html), t(9;14)(q34.3;q11.2) that juxtaposes the intragenic regions of both NOTCH1 and TRAV. Long-distance inverse (LDI)-PCR confirmed and extended these findings, revealing tail-to-tail fusions of intron-27 of NOTCH1 at 138 516 818 and 138 516 905 bp, with 5'-TRAV40 (21 852 526 bp) and intron-1 of TRAV5 (21 287 494 bp) in HD-MAR and HT-1, respectively (Figures 1e and f, Supplementary Figure S1 A/B). t(9;14) in HD-MAR and HT-1 cells places NOTCH1, truncated inside HD (predicted 5 amino acids trans- of the S2 cleavage site), under transcriptional control of TRAV (Figure 1a). The TRAV-40 breakpoint in HD-MAR lies close to the proximal Eδ enhancer, whereas that in HT-1 at TRAV-5 lies ∼600 kbp upstream near a cluster of DNase-I hypersensitive sites known to drive oncogene transcription in T-ALL. Thus, both t(9;14) cell lines carry breakpoints located inside HD, in contrast with that lying upstream (cis-) of HD in t(7;9) SUP-T1 cells.1

Inhibiting cleavage by GS-dependence (GSi) treatment effected the accumulation of four ANK+ species (105–116 kDa) taken as NTM/NTM*I (Figure 3e brackets), and dissipation of ∼110 kDa TM/RAM+ (ICN1), that is, a picture consistent with interconversion. This result underlines the dependence of TM/RAM expression on GS activity in t(9;14) cells. A fifth truncated ∼100 kDa NTM/NTM*I accumulated in HT-1 cells (arrow). Immunostaining revealed greater accumulation of perimembraneous NOTCH1 at the expense of intranuclear forms in HD-MAR than in SUP-T1 (Figure 3f). Taken together, GSi treatments revealed increased dependence of intra-HD breakpoint cells on GS activity for NOTCH1 expression, signaling and proliferation. The enhanced TM/RAM epitope exposure of both t(9;14) cell lines (Figure 2a bottom) suggests a protein structural basis underlying the reduced dependence of GS cleavage on prior S2 cleavage owing to their adjacent breakpoints. The correlation of GS sensitivity with intra-HD breakpoint placement is consistent with data from a second t(7;9) cell line CUTLL1 with an intra-HD breakpoint, also sensitive to GSi.7

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Acknowledgements

We thank H Ben-Bassat and M Abe for HD-MAR and HT-1 cells, respectively, A Ferrando for reading the paper, and the José Carreras Leukemia Research Fund for support.

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  1. Department of Human and Animal Cell Cultures, DSMZ, Braunschweig, Germany

    S Suzuki, S Nagel, B Schneider, S Chen, M Kaufmann, H G Drexler & R A F MacLeod

  2. Center for Chronic Viral Diseases, Kagoshima Univ. Sch. Med. Dent. Sci., Kagoshima, Japan

    S Suzuki, K Uozumi & N Arima

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Correspondence to R A F MacLeod.

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Suzuki, S., Nagel, S., Schneider, B. et al. A second NOTCH1 chromosome rearrangement: t(9;14)(q34.3;q11.2) in T-cell neoplasia. Leukemia 23, 1003–1006 (2009). https://doi.org/10.1038/leu.2008.366

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