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Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis

Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis
Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis
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.
chronic lymphocytic leukemia, richter syndrome, immunoglobulin gene, intraclonal diversification, clonal evolution
0020-7136
3006-3010
Rossi, Davide
b4b2506d-794c-4c79-8b2d-6767554fd52a
Spina, Valeria
bb72602d-3d56-424f-b169-47377aef1d10
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Capello, Daniela
f4d381f4-aaa6-47ae-bebf-53b0aed65055
Fangazio, Marco
054da702-e7e5-4721-84f6-c0cca9abd043
Rasi, Silvia
13639ced-c17f-4350-87e4-fb670cee592b
Martini, Maurizio
f30d1b76-681f-47cb-ac9d-8405800c5674
Gattei, Valter
df828ae8-1b40-4acb-8908-5a6b3d16cf99
Ramponi, Antonio
606dc60d-e75f-4501-8cf7-b52ade09ae9b
Larocca, Luigi M.
9429df66-edeb-46d4-b148-bb5137d91c63
Bertoni, Francesco
13297a2f-854a-4841-a410-d6bfca8afee8
Gaidano, Gianluca
1a6a7107-107b-4891-82e0-5fedadd2f65a
Rossi, Davide
b4b2506d-794c-4c79-8b2d-6767554fd52a
Spina, Valeria
bb72602d-3d56-424f-b169-47377aef1d10
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Capello, Daniela
f4d381f4-aaa6-47ae-bebf-53b0aed65055
Fangazio, Marco
054da702-e7e5-4721-84f6-c0cca9abd043
Rasi, Silvia
13639ced-c17f-4350-87e4-fb670cee592b
Martini, Maurizio
f30d1b76-681f-47cb-ac9d-8405800c5674
Gattei, Valter
df828ae8-1b40-4acb-8908-5a6b3d16cf99
Ramponi, Antonio
606dc60d-e75f-4501-8cf7-b52ade09ae9b
Larocca, Luigi M.
9429df66-edeb-46d4-b148-bb5137d91c63
Bertoni, Francesco
13297a2f-854a-4841-a410-d6bfca8afee8
Gaidano, Gianluca
1a6a7107-107b-4891-82e0-5fedadd2f65a

Rossi, Davide, Spina, Valeria, Forconi, Francesco, Capello, Daniela, Fangazio, Marco, Rasi, Silvia, Martini, Maurizio, Gattei, Valter, Ramponi, Antonio, Larocca, Luigi M., Bertoni, Francesco and Gaidano, Gianluca (2012) Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis. International Journal of Cancer, 130 (12), 3006-3010. (doi:10.1002/ijc.26322). (PMID:21796624)

Record type: Article

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.

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e-pub ahead of print date: 25 August 2011
Published date: 15 June 2012
Keywords: chronic lymphocytic leukemia, richter syndrome, immunoglobulin gene, intraclonal diversification, clonal evolution
Organisations: Cancer Sciences

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Local EPrints ID: 358108
URI: https://eprints.soton.ac.uk/id/eprint/358108
ISSN: 0020-7136
PURE UUID: 4349a521-1d77-4135-b6e0-b406738c1f79

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Date deposited: 04 Oct 2013 10:27
Last modified: 16 Jul 2019 21:21

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Contributors

Author: Davide Rossi
Author: Valeria Spina
Author: Daniela Capello
Author: Marco Fangazio
Author: Silvia Rasi
Author: Maurizio Martini
Author: Valter Gattei
Author: Antonio Ramponi
Author: Luigi M. Larocca
Author: Francesco Bertoni
Author: Gianluca Gaidano

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