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1. Preclinical characterization and clinical trial of CFI-400945, a polo-like kinase 4 inhibitor, in patients with relapsed/refractory acute myeloid leukemia and higher-risk myelodysplastic neoplasms

Author

Murphy, Tracy, Mason, Jacqueline M., Leber, Brian, Bray, Mark R., Chan, Steven M., Gupta, Vikas, Khalaf, Dina, Maze, Dawn, McNamara, Caroline J., Schimmer, Aaron D., Schuh, Andre C., Sibai, Hassan, Trus, Michael, Valiquette, Debbie, Martin, Kylie, Nguyen, Linh, Li, Xuan, Mak, Tak W., Minden, Mark D., and Yee, Karen W. L.

Published
2024
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2. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms

Author

Alaggio, Rita, Amador, Catalina, Anagnostopoulos, Ioannis, Attygalle, Ayoma D, Araujo, Iguaracyra Barreto de Oliveira, Berti, Emilio, Bhagat, Govind, Borges, Anita Maria, Boyer, Daniel, Calaminici, Mariarita, Chadburn, Amy, Chan, John KC, Cheuk, Wah, Chng, Wee-Joo, Choi, John K, Chuang, Shih-Sung, Coupland, Sarah E, Czader, Magdalena, Dave, Sandeep S, de Jong, Daphne, Du, Ming-Qing, Elenitoba-Johnson, Kojo S, Ferry, Judith, Geyer, Julia, Gratzinger, Dita, Guitart, Joan, Gujral, Sumeet, Harris, Marian, Harrison, Christine J, Hartmann, Sylvia, Hochhaus, Andreas, Jansen, Patty M, Karube, Kennosuke, Kempf, Werner, Khoury, Joseph, Kimura, Hiroshi, Klapper, Wolfram, Kovach, Alexandra E, Kumar, Shaji, Lazar, Alexander J, Lazzi, Stefano, Leoncini, Lorenzo, Leung, Nelson, Leventaki, Vasiliki, Li, Xiao-Qiu, Lim, Megan S, Liu, Wei-Ping, Louissaint, Abner, Marcogliese, Andrea, Medeiros, L Jeffrey, Michal, Michael, Miranda, Roberto N, Mitteldorf, Christina, Montes-Moreno, Santiago, Morice, William, Nardi, Valentina, Naresh, Kikkeri N, Natkunam, Yasodha, Ng, Siok-Bian, Oschlies, Ilske, Ott, German, Parrens, Marie, Pulitzer, Melissa, Rajkumar, S Vincent, Rawstron, Andrew C, Rech, Karen, Rosenwald, Andreas, Said, Jonathan, Sarkozy, Clémentine, Sayed, Shahin, Saygin, Caner, Schuh, Anna, Sewell, William, Siebert, Reiner, Sohani, Aliyah R, Tooze, Reuben, Traverse-Glehen, Alexandra, Vega, Francisco, Vergier, Beatrice, Wechalekar, Ashutosh D, Wood, Brent, Xerri, Luc, and Xiao, Wenbin

Subjects
Cancer, Hematologic Neoplasms, Humans, Lymphoma, World Health Organization, Clinical Sciences, Oncology and Carcinogenesis, Immunology
Abstract

We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.

Published
2022

3. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms

Author

Khoury, Joseph D, Solary, Eric, Abla, Oussama, Akkari, Yassmine, Alaggio, Rita, Apperley, Jane F, Bejar, Rafael, Berti, Emilio, Busque, Lambert, Chan, John KC, Chen, Weina, Chen, Xueyan, Chng, Wee-Joo, Choi, John K, Colmenero, Isabel, Coupland, Sarah E, Cross, Nicholas CP, De Jong, Daphne, Elghetany, M Tarek, Takahashi, Emiko, Emile, Jean-Francois, Ferry, Judith, Fogelstrand, Linda, Fontenay, Michaela, Germing, Ulrich, Gujral, Sumeet, Haferlach, Torsten, Harrison, Claire, Hodge, Jennelle C, Hu, Shimin, Jansen, Joop H, Kanagal-Shamanna, Rashmi, Kantarjian, Hagop M, Kratz, Christian P, Li, Xiao-Qiu, Lim, Megan S, Loeb, Keith, Loghavi, Sanam, Marcogliese, Andrea, Meshinchi, Soheil, Michaels, Phillip, Naresh, Kikkeri N, Natkunam, Yasodha, Nejati, Reza, Ott, German, Padron, Eric, Patel, Keyur P, Patkar, Nikhil, Picarsic, Jennifer, Platzbecker, Uwe, Roberts, Irene, Schuh, Anna, Sewell, William, Siebert, Reiner, Tembhare, Prashant, Tyner, Jeffrey, Verstovsek, Srdan, Wang, Wei, Wood, Brent, Xiao, Wenbin, Yeung, Cecilia, and Hochhaus, Andreas

Subjects
Genetics, Human Genome, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Hematologic Neoplasms, Histiocytosis, Humans, World Health Organization, Clinical Sciences, Oncology and Carcinogenesis, Immunology
Abstract

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.

Published
2022

4. Correction: “The 5th edition of The World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms” Leukemia. 2022 Jul;36(7):1720–1748

Author

Alaggio, Rita, Amador, Catalina, Anagnostopoulos, Ioannis, Attygalle, Ayoma D., de Oliveira Araujo, Iguaracyra Barreto, Berti, Emilio, Bhagat, Govind, Borges, Anita Maria, Boyer, Daniel, Calaminici, Mariarita, Chadburn, Amy, Chan, John K. C., Cheuk, Wah, Chng, Wee-Joo, Choi, John K., Chuang, Shih-Sung, Coupland, Sarah E., Czader, Magdalena, Dave, Sandeep S., de Jong, Daphne, Di Napoli, Arianna, Du, Ming-Qing, Elenitoba-Johnson, Kojo S., Ferry, Judith, Geyer, Julia, Gratzinger, Dita, Guitart, Joan, Gujral, Sumeet, Harris, Marian, Harrison, Christine J., Hartmann, Sylvia, Hochhaus, Andreas, Jansen, Patty M., Karube, Kennosuke, Kempf, Werner, Khoury, Joseph, Kimura, Hiroshi, Klapper, Wolfram, Kovach, Alexandra E., Kumar, Shaji, Lazar, Alexander J., Lazzi, Stefano, Leoncini, Lorenzo, Leung, Nelson, Leventaki, Vasiliki, Li, Xiao-Qiu, Lim, Megan S., Liu, Wei-Ping, Louissaint, Jr, Abner, Marcogliese, Andrea, Medeiros, L. Jeffrey, Michal, Michael, Miranda, Roberto N., Mitteldorf, Christina, Montes-Moreno, Santiago, Morice, William, Nardi, Valentina, Naresh, Kikkeri N., Natkunam, Yasodha, Ng, Siok-Bian, Oschlies, Ilske, Ott, German, Parrens, Marie, Pulitzer, Melissa, Rajkumar, S. Vincent, Rawstron, Andrew C., Rech, Karen, Rosenwald, Andreas, Said, Jonathan, Sarkozy, Clémentine, Sayed, Shahin, Saygin, Caner, Schuh, Anna, Sewell, William, Siebert, Reiner, Sohani, Aliyah R., Suzuki, Ritsuro, Tooze, Reuben, Traverse-Glehen, Alexandra, Vega, Francisco, Vergier, Beatrice, Wechalekar, Ashutosh D., Wood, Brent, Xerri, Luc, and Xiao, Wenbin

Published
2023
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5. Asparaginase completion among adults including older patients with acute lymphoblastic leukemia treated with a modified DFCI protocol

Author

Perusini, Maria Agustina, Andrews, Claire, Eshetu, Atenafu G., Gupta, Vikas, Maze, Dawn, Yee, Karen W. L., Bankar, Aniket, Davidson, Marta B., Richard-Carpentier, Guillaume, Chan, Steven M., Schimmer, Aaron D., Sibai, Jad, Alharbi, Salman, Lucero, Josephine A., Linn, Swe Mar, Minden, Mark D., Schuh, Andre C., and Sibai, Hassan

Published
2024
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7. EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia

Author

Young, E, Noerenberg, D, Mansouri, L, Ljungström, V, Frick, M, Sutton, L-A, Blakemore, SJ, Galan-Sousa, J, Plevova, K, Baliakas, P, Rossi, D, Clifford, R, Roos-Weil, D, Navrkalova, V, Dörken, B, Schmitt, CA, Smedby, KE, Juliusson, G, Giacopelli, B, Blachly, JS, Belessi, C, Panagiotidis, P, Chiorazzi, N, Davi, F, Langerak, AW, Oscier, D, Schuh, A, Gaidano, G, Ghia, P, Xu, W, Fan, L, Bernard, OA, Nguyen-Khac, F, Rassenti, L, Li, J, Kipps, TJ, Stamatopoulos, K, Pospisilova, S, Zenz, T, Oakes, CC, Strefford, JC, Rosenquist, R, and Damm, F

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Oncology and Carcinogenesis, Hematology, Cancer, Lymphoma, Lymphatic Research, Clinical Research, Health Disparities, Rare Diseases, Genetics, 4.1 Discovery and preclinical testing of markers and technologies, 2.1 Biological and endogenous factors, Adult, Aged, Early Growth Response Protein 2, Female, Genes, p53, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Mutation, Proportional Hazards Models, Clinical Sciences, Immunology, Cardiovascular medicine and haematology, Clinical sciences, Oncology and carcinogenesis
Abstract

Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.

Published
2017

8. SF3B1 mutations induce R-loop accumulation and DNA damage in MDS and leukemia cells with therapeutic implications

Author

Singh, Shalini, Ahmed, Doaa, Dolatshad, Hamid, Tatwavedi, Dharamveer, Schulze, Ulrike, Sanchi, Andrea, Ryley, Sarah, Dhir, Ashish, Carpenter, Lee, Watt, Suzanne M., Roberts, David J., Abdel-Aal, Amal M., Sayed, Sohair K., Mohamed, Somaia A., Schuh, Anna, Vyas, Paresh, Killick, Sally, Kotini, Andriana G., Papapetrou, Eirini P., Wiseman, Daniel H., Pellagatti, Andrea, and Boultwood, Jacqueline

Published
2020
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9. Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial

Author

Blakemore, Stuart J., Clifford, Ruth, Parker, Helen, Antoniou, Pavlos, Stec-Dziedzic, Ewa, Larrayoz, Marta, Davis, Zadie, Kadalyayil, Latha, Colins, Andrew, Robbe, Pauline, Vavoulis, Dimitris, Forster, Jade, Carr, Louise, Morilla, Ricardo, Else, Monica, Bryant, Dean, McCarthy, Helen, Walewska, Renata J., Steele, Andrew J., Chan, Jacqueline, Speight, Graham, Stankovic, Tanja, Cragg, Mark S., Catovsky, Daniel, Oscier, David G., Rose-Zerilli, Matthew J. J., Schuh, Anna, and Strefford, Jonathan C.

Published
2020
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10. Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit

Author

Cucco, Francesco, Barrans, Sharon, Sha, Chulin, Clipson, Alexandra, Crouch, Simon, Dobson, Rachel, Chen, Zi, Thompson, Joe Sneath, Care, Matthew A., Cummin, Thomas, Caddy, Josh, Liu, Hongxiang, Robinson, Anne, Schuh, Anna, Fitzgibbon, Jude, Painter, Daniel, Smith, Alexandra, Roman, Eve, Tooze, Reuben, Burton, Catherine, Davies, Andrew J., Westhead, David R., Johnson, Peter W. M., and Du, Ming-Qing

Published
2020
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23. Preclinical characterization and clinical trial of CFI-400945, a polo-like kinase 4 inhibitor, in patients with relapsed/refractory acute myeloid leukemia and higher-risk myelodysplastic neoplasms

Author

Murphy, Tracy, Mason, Jacqueline M., Leber, Brian, Bray, Mark R., Chan, Steven M., Gupta, Vikas, Khalaf, Dina, Maze, Dawn, McNamara, Caroline J., Schimmer, Aaron D., Schuh, Andre C., Sibai, Hassan, Trus, Michael, Valiquette, Debbie, Martin, Kylie, Nguyen, Linh, Li, Xuan, Mak, Tak W., Minden, Mark D., and Yee, Karen W. L.

Abstract

CFI-400945 is a selective oral polo-like kinase 4 (PLK4) inhibitor that regulates centriole duplication. PLK4 is aberrantly expressed in patients with acute myeloid leukemia (AML). Preclinical studies indicate that CFI-400945 has potent in vivo efficacy in hematological malignancies and xenograft models, with activity in cells harboring TP53mutations. In this phase 1 study in very high-risk patients with relapsed/refractory AML and myelodysplastic syndrome (MDS) (NCT03187288), 13 patients were treated with CFI-400945 continuously in dose escalation from 64 mg/day to 128 mg/day. Three of the 9 efficacy evaluable AML patients achieved complete remission (CR). Two of 4 AML patients (50%) with TP53mutations and complex monosomal karyotype achieved a CR with 1 patient proceeding to allogenic stem cell transplant. A third patient with TP53mutated AML had a significant reduction in marrow blasts by > 50% with an improvement in neutrophil and platelet counts. Responses were observed after 1 cycle of therapy. Dose-limiting toxicity was enteritis/colitis. A monotherapy and combination therapy study with a newer crystal form of CFI-400945 in patients with AML, MDS and chronic myelomonocytic leukemia (CMML) is ongoing (NCT04730258).

Published
2023
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25. SF3B1mutations induce R-loop accumulation and DNA damage in MDS and leukemia cells with therapeutic implications

Author

Singh, Shalini, Ahmed, Doaa, Dolatshad, Hamid, Tatwavedi, Dharamveer, Schulze, Ulrike, Sanchi, Andrea, Ryley, Sarah, Dhir, Ashish, Carpenter, Lee, Watt, Suzanne M., Roberts, David J., Abdel-Aal, Amal M., Sayed, Sohair K., Mohamed, Somaia A., Schuh, Anna, Vyas, Paresh, Killick, Sally, Kotini, Andriana G., Papapetrou, Eirini P., Wiseman, Daniel H., Pellagatti, Andrea, and Boultwood, Jacqueline

Published
2020
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26. Clinical significance of TP53, BIRC3, ATMand MAPK-ERKgenes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial

Author

Blakemore, Stuart J., Clifford, Ruth, Parker, Helen, Antoniou, Pavlos, Stec-Dziedzic, Ewa, Larrayoz, Marta, Davis, Zadie, Kadalyayil, Latha, Colins, Andrew, Robbe, Pauline, Vavoulis, Dimitris, Forster, Jade, Carr, Louise, Morilla, Ricardo, Else, Monica, Bryant, Dean, McCarthy, Helen, Walewska, Renata J., Steele, Andrew J., Chan, Jacqueline, Speight, Graham, Stankovic, Tanja, Cragg, Mark S., Catovsky, Daniel, Oscier, David G., Rose-Zerilli, Matthew J. J., Schuh, Anna, and Strefford, Jonathan C.

Abstract

Despite advances in chronic lymphocytic leukaemia (CLL) treatment, globally chemotherapy remains a central treatment modality, with chemotherapy trials representing an invaluable resource to explore disease-related/genetic features contributing to long-term outcomes. In 499 LRF CLL4 cases, a trial with >12 years follow-up, we employed targeted resequencing of 22 genes, identifying 623 mutations. After background mutation rate correction, 11/22 genes were recurrently mutated at frequencies between 3.6% (NFKBIE) and 24% (SF3B1). Mutations beyond Sanger resolution (<12% VAF) were observed in all genes, with KRASmutations principally composed of these low VAF variants. Firstly, employing orthogonal approaches to confirm <12% VAF TP53mutations, we assessed the clinical impact of TP53clonal architecture. Whilst ≥ 12% VAF TP53mut cases were associated with reduced PFS and OS, we could not demonstrate a difference between <12% VAF TP53mutations and either wild type or ≥12% VAF TP53mut cases. Secondly, we identified biallelic BIRC3lesions (mutation and deletion) as an independent marker of inferior PFS and OS. Finally, we observed that mutated MAPK-ERKgenes were independent markers of poor OS in multivariate survival analysis. In conclusion, our study supports using targeted resequencing of expanded gene panels to elucidate the prognostic impact of gene mutations.

Published
2020
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27. Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2double-hit

Author

Cucco, Francesco, Barrans, Sharon, Sha, Chulin, Clipson, Alexandra, Crouch, Simon, Dobson, Rachel, Chen, Zi, Thompson, Joe Sneath, Care, Matthew A., Cummin, Thomas, Caddy, Josh, Liu, Hongxiang, Robinson, Anne, Schuh, Anna, Fitzgibbon, Jude, Painter, Daniel, Smith, Alexandra, Roman, Eve, Tooze, Reuben, Burton, Catherine, Davies, Andrew J., Westhead, David R., Johnson, Peter W. M., and Du, Ming-Qing

Abstract

Using a Burkitt lymphoma-like gene expression signature, we recently defined a high-risk molecular high-grade (MHG) group mainly within germinal centre B-cell like diffuse large B-cell lymphomas (GCB-DLBCL), which was enriched for MYC/BCL2double-hit (MYC/BCL2-DH). The genetic basis underlying MHG-DLBCL and their aggressive clinical behaviour remain unknown. We investigated 697 cases of DLBCL, particularly those with MYC/BCL2-DH (n= 62) by targeted sequencing and gene expression profiling. We showed that DLBCL with MYC/BCL2-DH, and those with BCL2translocation, harbour the characteristic mutation signatures that are associated with follicular lymphoma and its high-grade transformation. We identified frequent MYChotspot mutations that affect the phosphorylation site (T58) and its adjacent amino acids, which are important for MYC protein degradation. These MYCmutations were seen in a subset of cases with MYCtranslocation, but predominantly in those of MHG. The mutations were more frequent in double-hit lymphomas with IG as the MYCtranslocation partner, and were associated with higher MYC protein expression and poor patient survival. DLBCL with MYC/BCL2-DH and those with BCL2translocation alone are most likely derived from follicular lymphoma or its precursor lesion, and acquisition of MYCpathogenic mutations may augment MYC function, resulting in aggressive clinical behaviour.

Published
2020
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28. Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmutand IgHVunmutsubgroups

Author

Burns, A, Alsolami, R, Becq, J, Stamatopoulos, B, Timbs, A, Bruce, D, Robbe, P, Vavoulis, D, Clifford, R, Cabes, M, Dreau, H, Taylor, J, Knight, S J L, Mansson, R, Bentley, D, Beekman, R, Martín-Subero, J I, Campo, E, Houlston, R S, Ridout, K E, and Schuh, A

Abstract

Chronic lymphocytic leukaemia (CLL) consists of two biologically and clinically distinct subtypes defined by the abundance of somatic hypermutation (SHM) affecting the Ig variable heavy-chain locus (IgHV). The molecular mechanisms underlying these subtypes are incompletely understood. Here, we present a comprehensive whole-genome sequencing analysis of somatically acquired genetic events from 46 CLL patients, including a systematic comparison of coding and non-coding single-nucleotide variants, copy number variants and structural variants, regions of kataegis and mutation signatures between IgHVmutand IgHVunmutsubtypes. We demonstrate that one-quarter of non-coding mutations in regions of kataegis outside the Ig loci are located in genes relevant to CLL. We show that non-coding mutations in ATM may negatively impact on ATM expression and find non-coding and regulatory region mutations in TCL1A, and in IgHVunmutCLL in IKZF3, SAMHD1,PAX5 and BIRC3. Finally, we show that IgHVunmutCLL is dominated by coding mutations in driver genes and an aging signature, whereas IgHVmutCLL has a high incidence of promoter and enhancer mutations caused by aberrant activation-induced cytidine deaminase activity. Taken together, our data support the hypothesis that differences in clinical outcome and biological characteristics between the two subgroups might reflect differences in mutation distribution, incidence and distinct underlying mutagenic mechanisms.

Published
2018
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29. EGR2mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia

Author

Young, E, Noerenberg, D, Mansouri, L, Ljungström, V, Frick, M, Sutton, L-A, Blakemore, S J, Galan-Sousa, J, Plevova, K, Baliakas, P, Rossi, D, Clifford, R, Roos-Weil, D, Navrkalova, V, Dörken, B, Schmitt, C A, Smedby, K E, Juliusson, G, Giacopelli, B, Blachly, J S, Belessi, C, Panagiotidis, P, Chiorazzi, N, Davi, F, Langerak, A W, Oscier, D, Schuh, A, Gaidano, G, Ghia, P, Xu, W, Fan, L, Bernard, O A, Nguyen-Khac, F, Rassenti, L, Li, J, Kipps, T J, Stamatopoulos, K, Pospisilova, S, Zenz, T, Oakes, C C, Strefford, J C, Rosenquist, R, and Damm, F

Abstract

Recurrent mutations within EGR2were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATMlesions (42%), TP53aberrations (18%) and NOTCH1/FBXW7mutations (16%). EGR2mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53aberrations. In summary, EGR2mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.

Published
2017
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30. Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia

Author

Parker, H, Rose-Zerilli, M J J, Larrayoz, M, Clifford, R, Edelmann, J, Blakemore, S, Gibson, J, Wang, J, Ljungström, V, Wojdacz, T K, Chaplin, T, Roghanian, A, Davis, Z, Parker, A, Tausch, E, Ntoufa, S, Ramos, S, Robbe, P, Alsolami, R, Steele, A J, Packham, G, Rodríguez-Vicente, A E, Brown, L, McNicholl, F, Forconi, F, Pettitt, A, Hillmen, P, Dyer, M, Cragg, M S, Chelala, C, Oakes, C C, Rosenquist, R, Stamatopoulos, K, Stilgenbauer, S, Knight, S, Schuh, A, Oscier, D G, and Strefford, J C

Abstract

Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumours including haematological malignancies. Using high-resolution single nucleotide polymorphism (SNP) arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukaemia (CLL) patients. Further validation in two independent cohorts showed that SETD2 deletions were associated with loss of TP53, genomic complexity and chromothripsis. With next-generation sequencing we detected mutations of SETD2 in an additional 3.8% of patients (23/602). In most cases, SETD2 deletions or mutations were often observed as a clonal event and always as a mono-allelic lesion, leading to reduced mRNA expression in SETD2-disrupted cases. Patients with SETD2 abnormalities and wild-type TP53 and ATM from five clinical trials employing chemotherapy or chemo-immunotherapy had reduced progression-free and overall survival compared with cases wild type for all three genes. Consistent with its postulated role as a tumour suppressor, our data highlight SETD2 aberration as a recurrent, early loss-of-function event in CLL pathobiology linked to aggressive disease.

Published
2016
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32. Correction: Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmutand IgHVunmutsubgroups

Author

Burns, A, Alsolami, R, Becq, J, Stamatopoulos, B, Timbs, A, Bruce, D, Robbe, P, Vavoulis, D, Clifford, R, Cabes, M, Dreau, H, Taylor, J, Knight, S J L, Mansson, R, Bentley, D, Beekman, R, Martín-Subero, J I, Campo, E, Houlston, R S, Ridout, K E, and Schuh, A

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019
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33. Erratum: Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmutand IgHVunmutsubgroups

Author

Burns, A, Alsolami, R, Becq, J, Stamatopoulos, B, Timbs, A, Bruce, D, Robbe, P, Vavoulis, D, Clifford, R, Cabes, M, Dreau, H, Taylor, J, Knight, S J L, Mansson, R, Bentley, D, Beekman, R, Martín-Subero, J I, Campo, E, Houlston, R S, Ridout, K E, and Schuh, A

Abstract

Correction to: Leukemia (2018) 32, 332–342; doi: 10.1038/leu.2017.177; published online 27 June 2017 Since the publication of this article, the authors have identified an omission in their paper, namely that two contributing authors were not included in the author list: B Stamatopoulos1, R Clifford2

Published
2018
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