Recurrent MSCE116K mutations in ALK-negative anaplastic large cell lymphoma

Rebecca Luchtel, Michael T. Zimmermann, Guangzhen Hu, Surendra Dasari, Manli Jiang, Naoki Oishi, Hailey K. Jacobs, Yu Zeng, Tanya Hundal, Karen L. Rech, Rhett P. Ketterling, Jeong Heon Lee, Bruce W. Eckloff, Huihuang Yan, Krutika S. Gaonkar, Shulan Tian, Zhenqing Ye, Marshall E. Kadin, Jagmohan Sidhu, Liuyan JiangJesse Voss, Brian K. Link, Sergei I. Syrbu, Fabio Facchetti, Nabila Bennani, Susan L. Slager, Tamas Ordog, Jean Pierre Kocher, James R. Cerhan, Stephen M. Ansell, Andrew L. Feldman

Research output: Contribution to journalArticle

Abstract

Anaplastic large cell lymphomas (ALCLs) represent a relatively common group of T-cell non- Hodgkin lymphomas (T-NHLs) that are unified by similar pathologic features but demonstrate marked genetic heterogeneity. ALCLs are broadly classified as being anaplastic lymphoma kinase (ALK)+ or ALK-, based on the presence or absence of ALK rearrangements. Exome sequencing of 62 T-NHLs identified a previously unreported recurrent mutation in the musculin gene, MSCE116K, exclusively in ALK- ALCLs. Additional sequencing for a total of 238 T-NHLs confirmed the specificity of MSCE116K for ALK- ALCL and further demonstrated that 14 of 15 mutated cases (93%) had coexisting DUSP22 rearrangements. Musculin is a basic helix-loop-helix (bHLH) transcription factor that heterodimerizes with other bHLH proteins to regulate lymphocyte development. The E116K mutation localized to the DNA binding domain of musculin and permitted formation of musculin-bHLH heterodimers but prevented their binding to authentic target sequence. Functional analysis showed MSCE116K acted in a dominant-negative fashion, reversing wild-type musculininduced repression of MYC and cell cycle inhibition. Chromatin immunoprecipitation- sequencing and transcriptome analysis identified the cell cycle regulatory gene E2F2 as a direct transcriptional target of musculin. MSCE116K reversed E2F2-induced cell cycle arrest and promoted expression of the CD30-IRF4-MYC axis, whereas its expression was reciprocally induced by binding of IRF4 to the MSC promoter. Finally, ALCL cells expressing MSCE116K were preferentially targeted by the BET inhibitor JQ1. These findings identify a novel recurrent MSC mutation as a key driver of the CD30-IRF4-MYC axis and cell cycle progression in a unique subset of ALCLs.

Original languageEnglish (US)
Pages (from-to)2776-2789
Number of pages14
JournalBlood
Volume133
Issue number26
DOIs
StatePublished - Jun 27 2019

Fingerprint

Anaplastic Large-Cell Lymphoma
Cells
T-cells
Mutation
T-Cell Lymphoma
Non-Hodgkin's Lymphoma
Genes
Cell Cycle
Basic Helix-Loop-Helix Transcription Factors
Functional analysis
Lymphocytes
Exome
cdc Genes
Genetic Heterogeneity
Chromatin Immunoprecipitation
Chromatin
Gene Expression Profiling
Regulator Genes
Cell Cycle Checkpoints
anaplastic lymphoma kinase

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Luchtel, R., Zimmermann, M. T., Hu, G., Dasari, S., Jiang, M., Oishi, N., ... Feldman, A. L. (2019). Recurrent MSCE116K mutations in ALK-negative anaplastic large cell lymphoma. Blood, 133(26), 2776-2789. https://doi.org/10.1182/blood.2019000626

Recurrent MSCE116K mutations in ALK-negative anaplastic large cell lymphoma. / Luchtel, Rebecca; Zimmermann, Michael T.; Hu, Guangzhen; Dasari, Surendra; Jiang, Manli; Oishi, Naoki; Jacobs, Hailey K.; Zeng, Yu; Hundal, Tanya; Rech, Karen L.; Ketterling, Rhett P.; Lee, Jeong Heon; Eckloff, Bruce W.; Yan, Huihuang; Gaonkar, Krutika S.; Tian, Shulan; Ye, Zhenqing; Kadin, Marshall E.; Sidhu, Jagmohan; Jiang, Liuyan; Voss, Jesse; Link, Brian K.; Syrbu, Sergei I.; Facchetti, Fabio; Bennani, Nabila; Slager, Susan L.; Ordog, Tamas; Kocher, Jean Pierre; Cerhan, James R.; Ansell, Stephen M.; Feldman, Andrew L.

In: Blood, Vol. 133, No. 26, 27.06.2019, p. 2776-2789.

Research output: Contribution to journalArticle

Luchtel, R, Zimmermann, MT, Hu, G, Dasari, S, Jiang, M, Oishi, N, Jacobs, HK, Zeng, Y, Hundal, T, Rech, KL, Ketterling, RP, Lee, JH, Eckloff, BW, Yan, H, Gaonkar, KS, Tian, S, Ye, Z, Kadin, ME, Sidhu, J, Jiang, L, Voss, J, Link, BK, Syrbu, SI, Facchetti, F, Bennani, N, Slager, SL, Ordog, T, Kocher, JP, Cerhan, JR, Ansell, SM & Feldman, AL 2019, 'Recurrent MSCE116K mutations in ALK-negative anaplastic large cell lymphoma', Blood, vol. 133, no. 26, pp. 2776-2789. https://doi.org/10.1182/blood.2019000626
Luchtel R, Zimmermann MT, Hu G, Dasari S, Jiang M, Oishi N et al. Recurrent MSCE116K mutations in ALK-negative anaplastic large cell lymphoma. Blood. 2019 Jun 27;133(26):2776-2789. https://doi.org/10.1182/blood.2019000626
Luchtel, Rebecca ; Zimmermann, Michael T. ; Hu, Guangzhen ; Dasari, Surendra ; Jiang, Manli ; Oishi, Naoki ; Jacobs, Hailey K. ; Zeng, Yu ; Hundal, Tanya ; Rech, Karen L. ; Ketterling, Rhett P. ; Lee, Jeong Heon ; Eckloff, Bruce W. ; Yan, Huihuang ; Gaonkar, Krutika S. ; Tian, Shulan ; Ye, Zhenqing ; Kadin, Marshall E. ; Sidhu, Jagmohan ; Jiang, Liuyan ; Voss, Jesse ; Link, Brian K. ; Syrbu, Sergei I. ; Facchetti, Fabio ; Bennani, Nabila ; Slager, Susan L. ; Ordog, Tamas ; Kocher, Jean Pierre ; Cerhan, James R. ; Ansell, Stephen M. ; Feldman, Andrew L. / Recurrent MSCE116K mutations in ALK-negative anaplastic large cell lymphoma. In: Blood. 2019 ; Vol. 133, No. 26. pp. 2776-2789.
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title = "Recurrent MSCE116K mutations in ALK-negative anaplastic large cell lymphoma",
abstract = "Anaplastic large cell lymphomas (ALCLs) represent a relatively common group of T-cell non- Hodgkin lymphomas (T-NHLs) that are unified by similar pathologic features but demonstrate marked genetic heterogeneity. ALCLs are broadly classified as being anaplastic lymphoma kinase (ALK)+ or ALK-, based on the presence or absence of ALK rearrangements. Exome sequencing of 62 T-NHLs identified a previously unreported recurrent mutation in the musculin gene, MSCE116K, exclusively in ALK- ALCLs. Additional sequencing for a total of 238 T-NHLs confirmed the specificity of MSCE116K for ALK- ALCL and further demonstrated that 14 of 15 mutated cases (93{\%}) had coexisting DUSP22 rearrangements. Musculin is a basic helix-loop-helix (bHLH) transcription factor that heterodimerizes with other bHLH proteins to regulate lymphocyte development. The E116K mutation localized to the DNA binding domain of musculin and permitted formation of musculin-bHLH heterodimers but prevented their binding to authentic target sequence. Functional analysis showed MSCE116K acted in a dominant-negative fashion, reversing wild-type musculininduced repression of MYC and cell cycle inhibition. Chromatin immunoprecipitation- sequencing and transcriptome analysis identified the cell cycle regulatory gene E2F2 as a direct transcriptional target of musculin. MSCE116K reversed E2F2-induced cell cycle arrest and promoted expression of the CD30-IRF4-MYC axis, whereas its expression was reciprocally induced by binding of IRF4 to the MSC promoter. Finally, ALCL cells expressing MSCE116K were preferentially targeted by the BET inhibitor JQ1. These findings identify a novel recurrent MSC mutation as a key driver of the CD30-IRF4-MYC axis and cell cycle progression in a unique subset of ALCLs.",
author = "Rebecca Luchtel and Zimmermann, {Michael T.} and Guangzhen Hu and Surendra Dasari and Manli Jiang and Naoki Oishi and Jacobs, {Hailey K.} and Yu Zeng and Tanya Hundal and Rech, {Karen L.} and Ketterling, {Rhett P.} and Lee, {Jeong Heon} and Eckloff, {Bruce W.} and Huihuang Yan and Gaonkar, {Krutika S.} and Shulan Tian and Zhenqing Ye and Kadin, {Marshall E.} and Jagmohan Sidhu and Liuyan Jiang and Jesse Voss and Link, {Brian K.} and Syrbu, {Sergei I.} and Fabio Facchetti and Nabila Bennani and Slager, {Susan L.} and Tamas Ordog and Kocher, {Jean Pierre} and Cerhan, {James R.} and Ansell, {Stephen M.} and Feldman, {Andrew L.}",
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T1 - Recurrent MSCE116K mutations in ALK-negative anaplastic large cell lymphoma

AU - Luchtel, Rebecca

AU - Zimmermann, Michael T.

AU - Hu, Guangzhen

AU - Dasari, Surendra

AU - Jiang, Manli

AU - Oishi, Naoki

AU - Jacobs, Hailey K.

AU - Zeng, Yu

AU - Hundal, Tanya

AU - Rech, Karen L.

AU - Ketterling, Rhett P.

AU - Lee, Jeong Heon

AU - Eckloff, Bruce W.

AU - Yan, Huihuang

AU - Gaonkar, Krutika S.

AU - Tian, Shulan

AU - Ye, Zhenqing

AU - Kadin, Marshall E.

AU - Sidhu, Jagmohan

AU - Jiang, Liuyan

AU - Voss, Jesse

AU - Link, Brian K.

AU - Syrbu, Sergei I.

AU - Facchetti, Fabio

AU - Bennani, Nabila

AU - Slager, Susan L.

AU - Ordog, Tamas

AU - Kocher, Jean Pierre

AU - Cerhan, James R.

AU - Ansell, Stephen M.

AU - Feldman, Andrew L.

PY - 2019/6/27

Y1 - 2019/6/27

N2 - Anaplastic large cell lymphomas (ALCLs) represent a relatively common group of T-cell non- Hodgkin lymphomas (T-NHLs) that are unified by similar pathologic features but demonstrate marked genetic heterogeneity. ALCLs are broadly classified as being anaplastic lymphoma kinase (ALK)+ or ALK-, based on the presence or absence of ALK rearrangements. Exome sequencing of 62 T-NHLs identified a previously unreported recurrent mutation in the musculin gene, MSCE116K, exclusively in ALK- ALCLs. Additional sequencing for a total of 238 T-NHLs confirmed the specificity of MSCE116K for ALK- ALCL and further demonstrated that 14 of 15 mutated cases (93%) had coexisting DUSP22 rearrangements. Musculin is a basic helix-loop-helix (bHLH) transcription factor that heterodimerizes with other bHLH proteins to regulate lymphocyte development. The E116K mutation localized to the DNA binding domain of musculin and permitted formation of musculin-bHLH heterodimers but prevented their binding to authentic target sequence. Functional analysis showed MSCE116K acted in a dominant-negative fashion, reversing wild-type musculininduced repression of MYC and cell cycle inhibition. Chromatin immunoprecipitation- sequencing and transcriptome analysis identified the cell cycle regulatory gene E2F2 as a direct transcriptional target of musculin. MSCE116K reversed E2F2-induced cell cycle arrest and promoted expression of the CD30-IRF4-MYC axis, whereas its expression was reciprocally induced by binding of IRF4 to the MSC promoter. Finally, ALCL cells expressing MSCE116K were preferentially targeted by the BET inhibitor JQ1. These findings identify a novel recurrent MSC mutation as a key driver of the CD30-IRF4-MYC axis and cell cycle progression in a unique subset of ALCLs.

AB - Anaplastic large cell lymphomas (ALCLs) represent a relatively common group of T-cell non- Hodgkin lymphomas (T-NHLs) that are unified by similar pathologic features but demonstrate marked genetic heterogeneity. ALCLs are broadly classified as being anaplastic lymphoma kinase (ALK)+ or ALK-, based on the presence or absence of ALK rearrangements. Exome sequencing of 62 T-NHLs identified a previously unreported recurrent mutation in the musculin gene, MSCE116K, exclusively in ALK- ALCLs. Additional sequencing for a total of 238 T-NHLs confirmed the specificity of MSCE116K for ALK- ALCL and further demonstrated that 14 of 15 mutated cases (93%) had coexisting DUSP22 rearrangements. Musculin is a basic helix-loop-helix (bHLH) transcription factor that heterodimerizes with other bHLH proteins to regulate lymphocyte development. The E116K mutation localized to the DNA binding domain of musculin and permitted formation of musculin-bHLH heterodimers but prevented their binding to authentic target sequence. Functional analysis showed MSCE116K acted in a dominant-negative fashion, reversing wild-type musculininduced repression of MYC and cell cycle inhibition. Chromatin immunoprecipitation- sequencing and transcriptome analysis identified the cell cycle regulatory gene E2F2 as a direct transcriptional target of musculin. MSCE116K reversed E2F2-induced cell cycle arrest and promoted expression of the CD30-IRF4-MYC axis, whereas its expression was reciprocally induced by binding of IRF4 to the MSC promoter. Finally, ALCL cells expressing MSCE116K were preferentially targeted by the BET inhibitor JQ1. These findings identify a novel recurrent MSC mutation as a key driver of the CD30-IRF4-MYC axis and cell cycle progression in a unique subset of ALCLs.

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