Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

Anupama Reddy; Jenny Zhang; Nicholas S Davis; Andrea B Moffitt; Cassandra L Love; Alexander Waldrop; Sirpa Leppa; Annika Pasanen; Leo Meriranta; Marja-Liisa Karjalainen-Lindsberg; Peter Nørgaard; Mette Pedersen; Anne O Gang; Estrid Høgdall; Tayla B Heavican; Waseem Lone; Javeed Iqbal; Qiu Qin; Guojie Li; So Young Kim; Jane Healy; Kristy L Richards; Yuri Fedoriw; Leon Bernal-Mizrachi; Jean L Koff; Ashley D Staton; Christopher R Flowers; Ora Paltiel; Neta Goldschmidt; Maria Calaminici; Andrew Clear; John Gribben; Evelyn Nguyen; Magdalena B Czader; Sarah L Ondrejka; Angela Collie; Eric D Hsi; Eric Tse; Rex K H Au-Yeung; Yok-Lam Kwong; Gopesh Srivastava; William W L Choi; Andrew M Evens; Monika Pilichowska; Manju Sengar; Nishitha Reddy; Shaoying Li; Amy Chadburn; Leo I Gordon; Elaine S Jaffe; Shawn Levy; Rachel Rempel; Tiffany Tzeng; Lanie E. Happ; Tushar Dave; Deepthi Rajagopalan; Jyotishka Datta; David B. Dunson; Sandeep S. Dave

doi:10.1016/j.cell.2017.09.027

Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

Anupama Reddy, Jenny Zhang, Nicholas S Davis, Andrea B Moffitt, Cassandra L Love, Alexander Waldrop, Sirpa Leppa, Annika Pasanen, Leo Meriranta, Marja-Liisa Karjalainen-Lindsberg, Peter Nørgaard, Mette Pedersen, Anne O Gang, Estrid Høgdall, Tayla B Heavican, Waseem Lone, Javeed Iqbal, Qiu Qin, Guojie Li, So Young KimJane Healy, Kristy L Richards, Yuri Fedoriw, Leon Bernal-Mizrachi, Jean L Koff, Ashley D Staton, Christopher R Flowers, Ora Paltiel, Neta Goldschmidt, Maria Calaminici, Andrew Clear, John Gribben, Evelyn Nguyen, Magdalena B Czader, Sarah L Ondrejka, Angela Collie, Eric D Hsi, Eric Tse, Rex K H Au-Yeung, Yok-Lam Kwong, Gopesh Srivastava, William W L Choi, Andrew M Evens, Monika Pilichowska, Manju Sengar, Nishitha Reddy, Shaoying Li, Amy Chadburn, Leo I Gordon, Elaine S Jaffe, Shawn Levy, Rachel Rempel, Tiffany Tzeng, Lanie E. Happ, Tushar Dave, Deepthi Rajagopalan, Jyotishka Datta, David B. Dunson, Sandeep S. Dave

Department of Clinical Medicine

341 Citations (Scopus)

Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease. An integrative analysis in 1,001 newly diagnosed DLBCL patients identifies 150 genetic drivers with functional characterization using an unbiased CRISPR screen in DLBCL cell lines and connects with clinical outcome.

Original language	English
Journal	Cell
Volume	171
Issue number	2
Pages (from-to)	481-494.e15
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2017.09.027
Publication status	Published - 5 Oct 2017

Keywords

Antineoplastic Agents/administration & dosage
CRISPR-Cas Systems
Cell Line, Tumor
Cells, Cultured
Exome
Female
Gene Expression Profiling
Humans
Lymphoma, Large B-Cell, Diffuse/drug therapy
Male
Rituximab/administration & dosage

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2017.09.027

http://www.cell.com/article/S0092867417311212/pdf

Cite this

Reddy, A., Zhang, J., Davis, N. S., Moffitt, A. B., Love, C. L., Waldrop, A., Leppa, S., Pasanen, A., Meriranta, L., Karjalainen-Lindsberg, M.-L., Nørgaard, P., Pedersen, M., Gang, A. O., Høgdall, E., Heavican, T. B., Lone, W., Iqbal, J., Qin, Q., Li, G., ... Dave, S. S. (2017). Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma. Cell, 171(2), 481-494.e15. https://doi.org/10.1016/j.cell.2017.09.027

Reddy, A, Zhang, J, Davis, NS, Moffitt, AB, Love, CL, Waldrop, A, Leppa, S, Pasanen, A, Meriranta, L, Karjalainen-Lindsberg, M-L, Nørgaard, P, Pedersen, M, Gang, AO, Høgdall, E, Heavican, TB, Lone, W, Iqbal, J, Qin, Q, Li, G, Kim, SY, Healy, J, Richards, KL, Fedoriw, Y, Bernal-Mizrachi, L, Koff, JL, Staton, AD, Flowers, CR, Paltiel, O, Goldschmidt, N, Calaminici, M, Clear, A, Gribben, J, Nguyen, E, Czader, MB, Ondrejka, SL, Collie, A, Hsi, ED, Tse, E, Au-Yeung, RKH, Kwong, Y-L, Srivastava, G, Choi, WWL, Evens, AM, Pilichowska, M, Sengar, M, Reddy, N, Li, S, Chadburn, A, Gordon, LI, Jaffe, ES, Levy, S, Rempel, R, Tzeng, T, Happ, LE, Dave, T, Rajagopalan, D, Datta, J, Dunson, DB & Dave, SS 2017, 'Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma', Cell, vol. 171, no. 2, pp. 481-494.e15. https://doi.org/10.1016/j.cell.2017.09.027

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title = "Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma",

abstract = "Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease. An integrative analysis in 1,001 newly diagnosed DLBCL patients identifies 150 genetic drivers with functional characterization using an unbiased CRISPR screen in DLBCL cell lines and connects with clinical outcome.",

keywords = "Antineoplastic Agents/administration & dosage, CRISPR-Cas Systems, Cell Line, Tumor, Cells, Cultured, Exome, Female, Gene Expression Profiling, Humans, Lymphoma, Large B-Cell, Diffuse/drug therapy, Male, Rituximab/administration & dosage",

author = "Anupama Reddy and Jenny Zhang and Davis, {Nicholas S} and Moffitt, {Andrea B} and Love, {Cassandra L} and Alexander Waldrop and Sirpa Leppa and Annika Pasanen and Leo Meriranta and Marja-Liisa Karjalainen-Lindsberg and Peter N{\o}rgaard and Mette Pedersen and Gang, {Anne O} and Estrid H{\o}gdall and Heavican, {Tayla B} and Waseem Lone and Javeed Iqbal and Qiu Qin and Guojie Li and Kim, {So Young} and Jane Healy and Richards, {Kristy L} and Yuri Fedoriw and Leon Bernal-Mizrachi and Koff, {Jean L} and Staton, {Ashley D} and Flowers, {Christopher R} and Ora Paltiel and Neta Goldschmidt and Maria Calaminici and Andrew Clear and John Gribben and Evelyn Nguyen and Czader, {Magdalena B} and Ondrejka, {Sarah L} and Angela Collie and Hsi, {Eric D} and Eric Tse and Au-Yeung, {Rex K H} and Yok-Lam Kwong and Gopesh Srivastava and Choi, {William W L} and Evens, {Andrew M} and Monika Pilichowska and Manju Sengar and Nishitha Reddy and Shaoying Li and Amy Chadburn and Gordon, {Leo I} and Jaffe, {Elaine S} and Shawn Levy and Rachel Rempel and Tiffany Tzeng and Happ, {Lanie E.} and Tushar Dave and Deepthi Rajagopalan and Jyotishka Datta and Dunson, {David B.} and Dave, {Sandeep S.}",

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T1 - Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

AU - Reddy, Anupama

AU - Zhang, Jenny

AU - Davis, Nicholas S

AU - Moffitt, Andrea B

AU - Love, Cassandra L

AU - Waldrop, Alexander

AU - Leppa, Sirpa

AU - Pasanen, Annika

AU - Meriranta, Leo

AU - Karjalainen-Lindsberg, Marja-Liisa

AU - Nørgaard, Peter

AU - Pedersen, Mette

AU - Gang, Anne O

AU - Høgdall, Estrid

AU - Heavican, Tayla B

AU - Lone, Waseem

AU - Iqbal, Javeed

AU - Qin, Qiu

AU - Li, Guojie

AU - Kim, So Young

AU - Healy, Jane

AU - Richards, Kristy L

AU - Fedoriw, Yuri

AU - Bernal-Mizrachi, Leon

AU - Koff, Jean L

AU - Staton, Ashley D

AU - Flowers, Christopher R

AU - Paltiel, Ora

AU - Goldschmidt, Neta

AU - Calaminici, Maria

AU - Clear, Andrew

AU - Gribben, John

AU - Nguyen, Evelyn

AU - Czader, Magdalena B

AU - Ondrejka, Sarah L

AU - Collie, Angela

AU - Hsi, Eric D

AU - Tse, Eric

AU - Au-Yeung, Rex K H

AU - Kwong, Yok-Lam

AU - Srivastava, Gopesh

AU - Choi, William W L

AU - Evens, Andrew M

AU - Pilichowska, Monika

AU - Sengar, Manju

AU - Reddy, Nishitha

AU - Li, Shaoying

AU - Chadburn, Amy

AU - Gordon, Leo I

AU - Jaffe, Elaine S

AU - Levy, Shawn

AU - Rempel, Rachel

AU - Tzeng, Tiffany

AU - Happ, Lanie E.

AU - Dave, Tushar

AU - Rajagopalan, Deepthi

AU - Datta, Jyotishka

AU - Dunson, David B.

AU - Dave, Sandeep S.

PY - 2017/10/5

Y1 - 2017/10/5

N2 - Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease. An integrative analysis in 1,001 newly diagnosed DLBCL patients identifies 150 genetic drivers with functional characterization using an unbiased CRISPR screen in DLBCL cell lines and connects with clinical outcome.

AB - Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease. An integrative analysis in 1,001 newly diagnosed DLBCL patients identifies 150 genetic drivers with functional characterization using an unbiased CRISPR screen in DLBCL cell lines and connects with clinical outcome.

KW - Antineoplastic Agents/administration & dosage

KW - CRISPR-Cas Systems

KW - Cell Line, Tumor

KW - Cells, Cultured

KW - Exome

KW - Female

KW - Gene Expression Profiling

KW - Humans

KW - Lymphoma, Large B-Cell, Diffuse/drug therapy

KW - Male

KW - Rituximab/administration & dosage

U2 - 10.1016/j.cell.2017.09.027

DO - 10.1016/j.cell.2017.09.027

M3 - Journal article

C2 - 28985567

SN - 0092-8674

VL - 171

SP - 481-494.e15

JO - Cell

JF - Cell

IS - 2