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Öztürk, Selcen; Paul, Yashna; Afzal, Saira; Gil-Farina, Irene; Jauch, Anna; Bruch, Peter-Martin; Kalter, Verena; Hanna, Bola; Arseni, Lavinia; Roessner, Philipp M.; Schmidt, Manfred; Stilgenbauer, Stephan; Dietrich, Sascha; Lichter, Peter; Zapatka, Marc; Seiffert, Martina

Longitudinal analyses of CLL in mice identify leukemia-related clonal changes including a Myc gain predicting poor outcome in patients

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  • Medientyp: E-Artikel
  • Titel: Longitudinal analyses of CLL in mice identify leukemia-related clonal changes including a Myc gain predicting poor outcome in patients
  • Beteiligte: Öztürk, Selcen; Paul, Yashna; Afzal, Saira; Gil-Farina, Irene; Jauch, Anna; Bruch, Peter-Martin; Kalter, Verena; Hanna, Bola; Arseni, Lavinia; Roessner, Philipp M.; Schmidt, Manfred; Stilgenbauer, Stephan; Dietrich, Sascha; Lichter, Peter; Zapatka, Marc; Seiffert, Martina
  • Erschienen: Springer Science and Business Media LLC, 2022
  • Erschienen in: Leukemia
  • Sprache: Englisch
  • DOI: 10.1038/s41375-021-01381-4
  • ISSN: 0887-6924; 1476-5551
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>Chronic lymphocytic leukemia (CLL) is a B-cell malignancy mainly occurring at an advanced age with no single major genetic driver. Transgenic expression of <jats:italic>TCL1</jats:italic> in B cells leads after a long latency to a CLL-like disease in aged Eµ-<jats:italic>TCL1</jats:italic> mice suggesting that <jats:italic>TCL1</jats:italic> overexpression is not sufficient for full leukemic transformation. In search for secondary genetic events and to elucidate the clonal evolution of CLL, we performed whole exome and B-cell receptor sequencing of longitudinal leukemia samples of Eµ-<jats:italic>TCL1</jats:italic> mice. We observed a B-cell receptor stereotypy, as described in patients, confirming that CLL is an antigen-driven disease. Deep sequencing showed that leukemia in Eµ-<jats:italic>TCL1</jats:italic> mice is mostly monoclonal. Rare oligoclonality was associated with inability of tumors to develop disease upon adoptive transfer in mice. In addition, we identified clonal changes and a sequential acquisition of mutations with known relevance in CLL, which highlights the genetic similarities and therefore, suitability of the Eµ-<jats:italic>TCL1</jats:italic> mouse model for progressive CLL. Among them, a recurrent gain of chromosome 15, where <jats:italic>Myc</jats:italic> is located, was identified in almost all tumors in Eµ-<jats:italic>TCL1</jats:italic> mice. Interestingly, amplification of 8q24, the chromosomal region containing <jats:italic>MYC</jats:italic> in humans, was associated with worse outcome of patients with CLL.</jats:p>