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<p>Activation of oncogenes by hijacking immunoglobulin gene loci (<i>IG</i>) enhancers via chromosomal translocation is a common pathogenetic mechanism in B-cell malignancies, affecting 5–10% of chronic lymphocytic leukemia (CLL). The oncogenic partners in many of these cases remain unidentified. Therefore, we conducted a comprehensive analysis of 144 CLL samples with <i>IGH-</i>translocation excluding <i>IGH</i>::<i>BCL2</i>, <i>IGH</i>::<i>CCND1</i>, <i>IGH</i>::<i>BCL3</i> and <i>IGH</i>::<i>MYC</i>. By combining fluorescence in situ hybridization (FISH) with whole-genome, targeted sequencing, and RNA expression profiling, we identified 25 <i>IG</i>-translocation partners; 12 were previously unreported. Of 142 cases, 107 (75%) displayed an unmutated <i>IGHV</i>. Genetic profiling showed a heterogenous distribution of chromosomal aberrations and recurrently mutated genes across the groups. Of 41 informative cases, 32 (78%) exhibited breakpoints driven by aberrant class-switch recombination (CSR), with prominent involvement of <i>IGHM</i> (9/41) and <i>IGHG3</i> (9/41). Three cases with unmutated <i>IGHV</i> carried a juxtaposition of the <i>IGH</i> locus 5’ to the intact <i>NKX2.6</i> gene in chromosome 8p21.2 due to illegitimate VDJ recombination, associated with significant ectopic upregulation of <i>NKX2.6</i> transcriptional expression (FDR &lt; 0.001, logFC: 15). Similarly, <i>METRNL</i>, located at the telomere of chromosome 17q25, was identified as a translocation partner gene in four cases. Our findings expand the spectrum of the oncogenic translocation partners targeting <i>IGH</i> in CLL.</p>

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The spectrum of immunoglobulin heavy chain enhancer hijacking in chronic lymphocytic leukemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月23日

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  • Cosima Drewes,
  • Cristina López,
  • Nnamdi Okeke,
  • Billy Jebaraj,
  • Christoph Wiegreffe,
  • Isabelle Kraus,
  • Sina Hillebrecht,
  • Amani Awada,
  • Susanne Bens,
  • Emil Chteinberg,
  • Barbara Eichhorst,
  • Sarah Datismann,
  • Martin J. S. Dyer,
  • Anja Fischer,
  • Kirsten Fischer,
  • Selina Glaser,
  • Michael Hallek,
  • Helene Kretzmer,
  • Anja Mottok,
  • Dominick Pfaff,
  • Karoline Schnitzler,
  • Jan P. Meier-Kolthoff,
  • Matthias Schlesner,
  • Christof Schneider,
  • Stefan Britsch,
  • Ole Ammerpohl,
  • Stephan Stilgenbauer,
  • Eugen Tausch,
  • Reiner Siebert

摘要

Activation of oncogenes by hijacking immunoglobulin gene loci (IG) enhancers via chromosomal translocation is a common pathogenetic mechanism in B-cell malignancies, affecting 5–10% of chronic lymphocytic leukemia (CLL). The oncogenic partners in many of these cases remain unidentified. Therefore, we conducted a comprehensive analysis of 144 CLL samples with IGH-translocation excluding IGH::BCL2, IGH::CCND1, IGH::BCL3 and IGH::MYC. By combining fluorescence in situ hybridization (FISH) with whole-genome, targeted sequencing, and RNA expression profiling, we identified 25 IG-translocation partners; 12 were previously unreported. Of 142 cases, 107 (75%) displayed an unmutated IGHV. Genetic profiling showed a heterogenous distribution of chromosomal aberrations and recurrently mutated genes across the groups. Of 41 informative cases, 32 (78%) exhibited breakpoints driven by aberrant class-switch recombination (CSR), with prominent involvement of IGHM (9/41) and IGHG3 (9/41). Three cases with unmutated IGHV carried a juxtaposition of the IGH locus 5’ to the intact NKX2.6 gene in chromosome 8p21.2 due to illegitimate VDJ recombination, associated with significant ectopic upregulation of NKX2.6 transcriptional expression (FDR < 0.001, logFC: 15). Similarly, METRNL, located at the telomere of chromosome 17q25, was identified as a translocation partner gene in four cases. Our findings expand the spectrum of the oncogenic translocation partners targeting IGH in CLL.