Premium
Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis
Author(s) -
Rossi Davide,
Spina Valeria,
Forconi Francesco,
Capello Daniela,
Fangazio Marco,
Rasi Silvia,
Martini Maurizio,
Gattei Valter,
Ramponi Antonio,
Larocca Luigi M.,
Bertoni Francesco,
Gaidano Gianluca
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.26322
Subject(s) - clone (java method) , biology , chronic lymphocytic leukemia , somatic evolution in cancer , leukemia , genetics , malignant transformation , lymphoma , gene , cancer research , immunology
Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia to aggressive lymphoma. We explored intraclonal diversification (ID) of immunoglobulin genes in order to ( i ) follow the evolutionary history of the RS clone ( ii ) compare the role of ID in clonally related RS vs . clonally unrelated cases. Most (10/11, 90.9%) clonally related RS stem from the predominant clone observed at CLL diagnosis. One single RS had a transformation pattern compatible with sequential evolution from a secondary CLL subclone. Once RS transformation had occurred, all secondary CLL subclones disappeared and were substituted by the dominant RS clone with its own descendants. These observations suggest that genetic lesions associated with RS transformation are acquired by a cell belonging to the original CLL clone, rather than being progressively accumulated by later CLL subclones. Accordingly, most (9/11, 81.1%) clonally related RS harbored a genetic lesion disrupting TP53 that was already present, though at subclonal levels, in 5/11 (45.5%) samples of the paired CLL phase. A fraction of clonally related RS switched off ID (4/11, 36.4%) or reduced the levels of ID (5/11, 45.4%) at transformation. Conversely, all clonally unrelated RS harbored ID and were characterized by a significantly higher mutation frequency compared to clonally related RS (median: 1.18 × 10 −3 vs . 0.13 × 10 ‐3 ; p =0.002). These data indicate that ( i ) clonally related RS stems from a cell that is already present within the initial CLL clone and ( ii ) clonally unrelated and clonally related RS are biologically distinct disorders also in terms of antigen affinity maturation.