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<p>The somatic hypermutation (SHM) status of immunoglobulin heavy-chain variable region gene (<i>IGHV</i>) is a well-established prognostic factor in chronic lymphocytic leukemia (CLL). We analyzed clonotypic <i>IGHV-IGHD-IGHJ</i> rearrangements in 4,251 newly diagnosed CLL patients in Poland (CLL-POL1), representing the largest national cohort to date. In total, 4,328 productive rearrangements were evaluated, of which 93% represented single clonal rearrangements. Additionally, double productive clonal rearrangements were identified in 76 cases (1.8%), of which 27 (35.5%) displayed discordant <i>IGHV</i> SHM status. Stereotyped B-cell receptor subsets were assigned to 10.6% of sequences, predominantly enriched in unmutated CLL (U-CLL) compared to mutated CLL (M-CLL) (72.8% vs. 22%; <i>p</i> &lt; 0.001). High-risk subsets (#1, #2, #5, #6, #59, #99) accounted for over a half of all stereotyped cases and were enriched in patients with <i>TP53</i> mutation. Most stereotyped subsets showed preferential or exclusive usage of specific <i>IGHV</i> genes. Integration of cytogenetic data revealed a strong enrichment of del(17p), del(11q), and trisomy 12 within U-CLL, whereas M-CLL was characterized by higher frequency of isolated del(13q). In summary, this study highlights distinct <i>IGHV-IGHD-IGHJ</i> pairing preferences and the heterogenous distribution of stereotyped subsets, revealing biologically meaningful associations with <i>TP53</i> mutation and cytogenetic profiles.</p>

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Integrated analysis of IGHV rearrangements and cytogenetic abnormalities in a large chronic lymphocytic leukemia cohort (CLL-POL1)

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月24日

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  • Paulina Własiuk,
  • Monika Szelest,
  • Magdalena Paziewska,
  • Agnieszka Karczmarczyk,
  • Sylwia Czekalska,
  • Magdalena Zawada,
  • Malwina Hut,
  • Oskar Przybyszewski,
  • Michał Soin,
  • Marzena Wojtaszewska,
  • Monika Pępek,
  • Agnieszka Kwak,
  • Małgorzata Pokrywka,
  • Piotr Wójcik,
  • Aleksandra Leszczyńska,
  • Justyna Bukowicz,
  • Wiktoria Szyca,
  • Ewelina Nowak-Ozimek,
  • Artur Kowalik,
  • Katarzyna Borg,
  • Hanna Makuch-Łasica,
  • Magdalena Wojtas,
  • Iwona Solarska,
  • Emilia Jaskuła,
  • Anna Sobczyńska-Konefał,
  • Klaudia Paruzel,
  • Agnieszka Chudy,
  • Ewa Wawrzyniak,
  • Tomasz Stokłosa,
  • Krzysztof Giannopoulos

摘要

The somatic hypermutation (SHM) status of immunoglobulin heavy-chain variable region gene (IGHV) is a well-established prognostic factor in chronic lymphocytic leukemia (CLL). We analyzed clonotypic IGHV-IGHD-IGHJ rearrangements in 4,251 newly diagnosed CLL patients in Poland (CLL-POL1), representing the largest national cohort to date. In total, 4,328 productive rearrangements were evaluated, of which 93% represented single clonal rearrangements. Additionally, double productive clonal rearrangements were identified in 76 cases (1.8%), of which 27 (35.5%) displayed discordant IGHV SHM status. Stereotyped B-cell receptor subsets were assigned to 10.6% of sequences, predominantly enriched in unmutated CLL (U-CLL) compared to mutated CLL (M-CLL) (72.8% vs. 22%; p < 0.001). High-risk subsets (#1, #2, #5, #6, #59, #99) accounted for over a half of all stereotyped cases and were enriched in patients with TP53 mutation. Most stereotyped subsets showed preferential or exclusive usage of specific IGHV genes. Integration of cytogenetic data revealed a strong enrichment of del(17p), del(11q), and trisomy 12 within U-CLL, whereas M-CLL was characterized by higher frequency of isolated del(13q). In summary, this study highlights distinct IGHV-IGHD-IGHJ pairing preferences and the heterogenous distribution of stereotyped subsets, revealing biologically meaningful associations with TP53 mutation and cytogenetic profiles.