The Light Chain IgLV3-21 Defines a New Poor Prognostic Subgroup
in Chronic Lymphocytic Leukemia: Results of a Multicenter Study

J 2018

The Light Chain IgLV3-21 Defines a New Poor Prognostic Subgroup in Chronic Lymphocytic Leukemia: Results of a Multicenter Study

STAMATOPOULOS, B., T. SMITH, E. CROMPOT, K. PIETERS, R. CLIFFORD et. al.

Základní údaje

Originální název

The Light Chain IgLV3-21 Defines a New Poor Prognostic Subgroup in Chronic Lymphocytic Leukemia: Results of a Multicenter Study

Autoři

STAMATOPOULOS, B. (826 Velká Británie a Severní Irsko), T. SMITH (826 Velká Británie a Severní Irsko), E. CROMPOT (56 Belgie), K. PIETERS (56 Belgie), R. CLIFFORD (826 Velká Británie a Severní Irsko), Marek MRÁZ (203 Česká republika, garant, domácí), P. ROBBE (826 Velká Británie a Severní Irsko), A. BURNS (826 Velká Británie a Severní Irsko), A. TIMBS (826 Velká Británie a Severní Irsko), D. BRUCE (826 Velká Británie a Severní Irsko), P. HILLMEN (826 Velká Británie a Severní Irsko), N. MEULEMAN (56 Belgie), P. MINEUR (56 Belgie), R. FIRESCU (56 Belgie), M. MAEREVOET (56 Belgie), V. DE WILDE (56 Belgie), A. EFIRA (56 Belgie), J. PHILIPPE (56 Belgie), B. VERHASSELT (56 Belgie), F. OFFNER (56 Belgie), D. SIMS (826 Velká Británie a Severní Irsko), A. HEGER (826 Velká Británie a Severní Irsko), H. DREAU (826 Velká Británie a Severní Irsko) a A. SCHUH (826 Velká Británie a Severní Irsko)

Vydání

Clinical cancer research, Philadelphia, AMER ASSOC CANCER RESEARCH, 2018, 1078-0432

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30204 Oncology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 8.911

Kód RIV

RIV/00216224:14740/18:00106953

Organizační jednotka

Středoevropský technologický institut

DOI

http://dx.doi.org/10.1158/1078-0432.CCR-18-0133

UT WoS

000447598900016

Klíčová slova anglicky

B-CELL RECEPTOR; ZAP70 MESSENGER-RNA; GENE-EXPRESSION; IG; LIGATION; CLL; QUANTIFICATION; STIMULATION; REVEALS

Štítky

rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 13. 3. 2019 17:11, Mgr. Pavla Foltynová, Ph.D.

Anotace

V originále

Purpose: Unmutated (UM) immunoglobulin heavy chain variable region (IgHV) status or IgHV3-21 gene usage is associated with poor prognosis in chronic lymphocytic leukemia (CLL) patients. Interestingly, IgHV3-21 is often coexpressed with light chain IgLV3-21, which is potentially able to trigger cell-autonomous BCR-mediated signaling. However, this light chain has never been characterized independently of the heavy chain IgHV3-21. Experimental Design: We performed total RNA sequencing in 32 patients and investigated IgLV3-21 prognostic impact in terms of treatment-free survival (TFS) and overall survival (OS) in 3 other independent cohorts for a total of 813 patients. IgLV3-21 presence was tested by real-time PCR and confirmed by Sanger sequencing. Results: Using total RNA sequencing to characterize 32 patients with high-risk CLL, we found a high frequency (28%) of IgLV3-21 rearrangements. Gene set enrichment analysis revealed that these patients express higher levels of genes responsible for ribosome biogenesis and translation initiation (P < 0.0001) as well as MYC target genes (P = 0.0003). Patients with IgLV3-21 rearrangements displayed a significantly shorter TFS and OS (P < 0.05), particularly those with IgHV mutation. In each of the three independent validation cohorts, we showed that IgLV3-21 rearrangements-similar to UM IgHV status-conferred poor prognosis compared with mutated IgHV (P < 0.0001). Importantly, we confirmed by multivariate analysis that this was independent of IgHV mutational status or subset # 2 stereotyped receptor (P < 0.0001). Conclusions: We have demonstrated for the first time that a light chain can affect CLL prognosis and that IgLV321 light chain usage defines a new subgroup of CLL patients with poor prognosis. (C) 2018 AACR.

Návaznosti

NV16-29622A, projekt VaV

Název: VLIV TERAPEUTICKÉ INHIBICE BCR SIGNALIZACE NA GENOVOU EXPRESI U B BUNĚČNÝCH MALIGNIT A JEJÍ PROGNOSTICKÝ A PREDIKTIVNÍ VÝZNAM

Citovat

STAMATOPOULOS, B., T. SMITH, E. CROMPOT, K. PIETERS, R. CLIFFORD, Marek MRÁZ, P. ROBBE, A. BURNS, A. TIMBS, D. BRUCE, P. HILLMEN, N. MEULEMAN, P. MINEUR, R. FIRESCU, M. MAEREVOET, V. DE WILDE, A. EFIRA, J. PHILIPPE, B. VERHASSELT, F. OFFNER, D. SIMS, A. HEGER, H. DREAU a A. SCHUH. The Light Chain IgLV3-21 Defines a New Poor Prognostic Subgroup in Chronic Lymphocytic Leukemia: Results of a Multicenter Study. Clinical cancer research. Philadelphia: AMER ASSOC CANCER RESEARCH, 2018, roč. 24, č. 20, s. 5048-5057. ISSN 1078-0432. Dostupné z: https://dx.doi.org/10.1158/1078-0432.CCR-18-0133.

@article{1477617,
   author = {Stamatopoulos, B. and Smith, T. and Crompot, E. and Pieters, K. and Clifford, R. and Mráz, Marek and Robbe, P. and Burns, A. and Timbs, A. and Bruce, D. and Hillmen, P. and Meuleman, N. and Mineur, P. and Firescu, R. and Maerevoet, M. and De Wilde, V. and Efira, A. and Philippe, J. and Verhasselt, B. and Offner, F. and Sims, D. and Heger, A. and Dreau, H. and Schuh, A.},
   article_location = {Philadelphia},
   article_number = {20},
   doi = {http://dx.doi.org/10.1158/1078-0432.CCR-18-0133},
   keywords = {B-CELL RECEPTOR; ZAP70 MESSENGER-RNA; GENE-EXPRESSION; IG; LIGATION; CLL; QUANTIFICATION; STIMULATION; REVEALS},
   language = {eng},
   issn = {1078-0432},
   journal = {Clinical cancer research},
   title = {The Light Chain IgLV3-21 Defines a New Poor Prognostic Subgroup in Chronic Lymphocytic Leukemia: Results of a Multicenter Study},
   url = {http://clincancerres.aacrjournals.org/content/24/20/5048},
   volume = {24},
   year = {2018}
}

TY  - JOUR
ID  - 1477617
AU  - Stamatopoulos, B. - Smith, T. - Crompot, E. - Pieters, K. - Clifford, R. - Mráz, Marek - Robbe, P. - Burns, A. - Timbs, A. - Bruce, D. - Hillmen, P. - Meuleman, N. - Mineur, P. - Firescu, R. - Maerevoet, M. - De Wilde, V. - Efira, A. - Philippe, J. - Verhasselt, B. - Offner, F. - Sims, D. - Heger, A. - Dreau, H. - Schuh, A.
PY  - 2018
TI  - The Light Chain IgLV3-21 Defines a New Poor Prognostic Subgroup in Chronic Lymphocytic Leukemia: Results of a Multicenter Study
JF  - Clinical cancer research
VL  - 24
IS  - 20
SP  - 5048-5057
EP  - 5048-5057
PB  - AMER ASSOC CANCER RESEARCH
SN  - 10780432
KW  - B-CELL RECEPTOR
KW  - ZAP70 MESSENGER-RNA
KW  - GENE-EXPRESSION
KW  - IG
KW  - LIGATION
KW  - CLL
KW  - QUANTIFICATION
KW  - STIMULATION
KW  - REVEALS
UR  - http://clincancerres.aacrjournals.org/content/24/20/5048
N2  - Purpose: Unmutated (UM) immunoglobulin heavy chain variable region (IgHV) status or IgHV3-21 gene usage is associated with poor prognosis in chronic lymphocytic leukemia (CLL) patients. Interestingly, IgHV3-21 is often coexpressed with light chain IgLV3-21, which is potentially able to trigger cell-autonomous BCR-mediated signaling. However, this light chain has never been characterized independently of the heavy chain IgHV3-21. Experimental Design: We performed total RNA sequencing in 32 patients and investigated IgLV3-21 prognostic impact in terms of treatment-free survival (TFS) and overall survival (OS) in 3 other independent cohorts for a total of 813 patients. IgLV3-21 presence was tested by real-time PCR and confirmed by Sanger sequencing. Results: Using total RNA sequencing to characterize 32 patients with high-risk CLL, we found a high frequency (28%) of IgLV3-21 rearrangements. Gene set enrichment analysis revealed that these patients express higher levels of genes responsible for ribosome biogenesis and translation initiation (P < 0.0001) as well as MYC target genes (P = 0.0003). Patients with IgLV3-21 rearrangements displayed a significantly shorter TFS and OS (P < 0.05), particularly those with IgHV mutation. In each of the three independent validation cohorts, we showed that IgLV3-21 rearrangements-similar to UM IgHV status-conferred poor prognosis compared with mutated IgHV (P < 0.0001). Importantly, we confirmed by multivariate analysis that this was independent of IgHV mutational status or subset # 2 stereotyped receptor (P < 0.0001). Conclusions: We have demonstrated for the first time that a light chain can affect CLL prognosis and that IgLV321 light chain usage defines a new subgroup of CLL patients with poor prognosis. (C) 2018 AACR.
ER  -

STAMATOPOULOS, B., T. SMITH, E. CROMPOT, K. PIETERS, R. CLIFFORD, Marek MRÁZ, P. ROBBE, A. BURNS, A. TIMBS, D. BRUCE, P. HILLMEN, N. MEULEMAN, P. MINEUR, R. FIRESCU, M. MAEREVOET, V. DE WILDE, A. EFIRA, J. PHILIPPE, B. VERHASSELT, F. OFFNER, D. SIMS, A. HEGER, H. DREAU a A. SCHUH. The Light Chain IgLV3-21 Defines a New Poor Prognostic Subgroup in Chronic Lymphocytic Leukemia: Results of a Multicenter Study. \textit{Clinical cancer research}. Philadelphia: AMER ASSOC CANCER RESEARCH, 2018, roč.~24, č.~20, s.~5048-5057. ISSN~1078-0432. Dostupné z: https://dx.doi.org/10.1158/1078-0432.CCR-18-0133.

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