title: Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis.
abstract: 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.
authors.affiliation: Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy. rossidav@med.unipmn.it
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.forename: Valeria
authors.initials: V
authors.lastname: Spina
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.forename: Daniela
authors.initials: D
authors.lastname: Capello
authors.forename: Marco
authors.initials: M
authors.lastname: Fangazio
authors.forename: Silvia
authors.initials: S
authors.lastname: Rasi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Martini
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
authors.forename: Antonio
authors.initials: A
authors.lastname: Ramponi
authors.forename: Luigi M
authors.initials: LM
authors.lastname: Larocca
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoni
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005803:Genes, Immunoglobulin; D016158:Genes, p53; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008223:Lymphoma / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D059645:Mutation Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D007136:Immunoglobulins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53