Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements

Rebecca Luchtel, Surendra Dasari, Naoki Oishi, Martin Bjerregård Pedersen, Guangzhen Hu, Karen L. Rech, Rhett P. Ketterling, Jagmohan Sidhu, Xueju Wang, Ryohei Katoh, Ahmet Dogan, N. Sertac Kip, Julie M Cunningham, Zhifu Sun, Saurabh Baheti, Julie C. Porcher, Jonathan W. Said, Liuyan Jiang, Stephen Jacques Hamilton-Dutoit, Michael Boe Møller & 10 others Peter Nørgaard, Nabila Bennani, Wee Joo Chng, Gaofeng Huang, Brian K. Link, Fabio Facchetti, James R Cerhan, Francesco D’Amore, Stephen Maxted Ansell, Andrew L Feldman

Research output: Contribution to journalArticle

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Abstract

Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell non-Hodgkin lymphomas broadly segregated into ALK-positive and ALK-negative types. Although ALK-positive ALCLs consistently bear rearrangements of the ALK tyrosine kinase gene, ALK-negative ALCLs are clinically and genetically heterogeneous. About 30% of ALK-negative ALCLs have rearrangements of DUSP22 and have excellent long-term outcomes with standard therapy. To better understand this group of tumors, we evaluated their molecular signature using gene expression profiling. DUSP22-rearranged ALCLs belonged to a distinct subset of ALCLs that lacked expression of genes associated with JAK-STAT3 signaling, a pathway contributing to growth in the majority of ALCLs. Reverse-phase protein array and immunohistochemical studies confirmed the lack of activated STAT3 in DUSP22-rearranged ALCLs. DUSP22-rearranged ALCLs also overexpressed immunogenic cancer-testis antigen (CTA) genes and showed marked DNA hypomethylation by reduced representation bi-sulfate sequencing and DNA methylation arrays. Pharmacologic DNA demethylation in ALCL cells recapitulated the overexpression of CTAs and other DUSP22 signature genes. In addition, DUSP22-rear-ranged ALCLs minimally expressed PD-L1 compared with other ALCLs, but showed high expression of the costimulatory gene CD58 and HLA class II. Taken together, these findings indicate that DUSP22 rearrangements define a molecularly distinct subgroup of ALCLs, and that immunogenic cues related to antigenicity, costimulatory molecule expression, and inactivity of the PD-1/PD-L1 immune checkpoint likely contribute to their favorable prognosis. More aggressive ALCLs might be pharmacologically reprogrammed to a DUSP22-like immunogenic molecular signature through the use of demethylating agents and/or immune checkpoint inhibitors.

Original languageEnglish (US)
Pages (from-to)1386-1398
Number of pages13
JournalBlood
Volume132
Issue number13
DOIs
StatePublished - Sep 27 2018

Fingerprint

Anaplastic Large-Cell Lymphoma
Cues
Genes
T-cells
DNA
Gene expression
Protein-Tyrosine Kinases
Sulfates
Tumors
Antigens
Molecules
Protein Array Analysis
MHC Class II Genes
T-Cell Lymphoma
Proteins
Testicular Neoplasms
Gene Expression Profiling
DNA Methylation
Oligonucleotide Array Sequence Analysis
Non-Hodgkin's Lymphoma

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements. / Luchtel, Rebecca; Dasari, Surendra; Oishi, Naoki; Pedersen, Martin Bjerregård; Hu, Guangzhen; Rech, Karen L.; Ketterling, Rhett P.; Sidhu, Jagmohan; Wang, Xueju; Katoh, Ryohei; Dogan, Ahmet; Kip, N. Sertac; Cunningham, Julie M; Sun, Zhifu; Baheti, Saurabh; Porcher, Julie C.; Said, Jonathan W.; Jiang, Liuyan; Hamilton-Dutoit, Stephen Jacques; Møller, Michael Boe; Nørgaard, Peter; Bennani, Nabila; Chng, Wee Joo; Huang, Gaofeng; Link, Brian K.; Facchetti, Fabio; Cerhan, James R; D’Amore, Francesco; Ansell, Stephen Maxted; Feldman, Andrew L.

In: Blood, Vol. 132, No. 13, 27.09.2018, p. 1386-1398.

Research output: Contribution to journalArticle

Luchtel, R, Dasari, S, Oishi, N, Pedersen, MB, Hu, G, Rech, KL, Ketterling, RP, Sidhu, J, Wang, X, Katoh, R, Dogan, A, Kip, NS, Cunningham, JM, Sun, Z, Baheti, S, Porcher, JC, Said, JW, Jiang, L, Hamilton-Dutoit, SJ, Møller, MB, Nørgaard, P, Bennani, N, Chng, WJ, Huang, G, Link, BK, Facchetti, F, Cerhan, JR, D’Amore, F, Ansell, SM & Feldman, AL 2018, 'Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements', Blood, vol. 132, no. 13, pp. 1386-1398. https://doi.org/10.1182/blood-2018-03-838524
Luchtel, Rebecca ; Dasari, Surendra ; Oishi, Naoki ; Pedersen, Martin Bjerregård ; Hu, Guangzhen ; Rech, Karen L. ; Ketterling, Rhett P. ; Sidhu, Jagmohan ; Wang, Xueju ; Katoh, Ryohei ; Dogan, Ahmet ; Kip, N. Sertac ; Cunningham, Julie M ; Sun, Zhifu ; Baheti, Saurabh ; Porcher, Julie C. ; Said, Jonathan W. ; Jiang, Liuyan ; Hamilton-Dutoit, Stephen Jacques ; Møller, Michael Boe ; Nørgaard, Peter ; Bennani, Nabila ; Chng, Wee Joo ; Huang, Gaofeng ; Link, Brian K. ; Facchetti, Fabio ; Cerhan, James R ; D’Amore, Francesco ; Ansell, Stephen Maxted ; Feldman, Andrew L. / Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements. In: Blood. 2018 ; Vol. 132, No. 13. pp. 1386-1398.
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title = "Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements",
abstract = "Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell non-Hodgkin lymphomas broadly segregated into ALK-positive and ALK-negative types. Although ALK-positive ALCLs consistently bear rearrangements of the ALK tyrosine kinase gene, ALK-negative ALCLs are clinically and genetically heterogeneous. About 30{\%} of ALK-negative ALCLs have rearrangements of DUSP22 and have excellent long-term outcomes with standard therapy. To better understand this group of tumors, we evaluated their molecular signature using gene expression profiling. DUSP22-rearranged ALCLs belonged to a distinct subset of ALCLs that lacked expression of genes associated with JAK-STAT3 signaling, a pathway contributing to growth in the majority of ALCLs. Reverse-phase protein array and immunohistochemical studies confirmed the lack of activated STAT3 in DUSP22-rearranged ALCLs. DUSP22-rearranged ALCLs also overexpressed immunogenic cancer-testis antigen (CTA) genes and showed marked DNA hypomethylation by reduced representation bi-sulfate sequencing and DNA methylation arrays. Pharmacologic DNA demethylation in ALCL cells recapitulated the overexpression of CTAs and other DUSP22 signature genes. In addition, DUSP22-rear-ranged ALCLs minimally expressed PD-L1 compared with other ALCLs, but showed high expression of the costimulatory gene CD58 and HLA class II. Taken together, these findings indicate that DUSP22 rearrangements define a molecularly distinct subgroup of ALCLs, and that immunogenic cues related to antigenicity, costimulatory molecule expression, and inactivity of the PD-1/PD-L1 immune checkpoint likely contribute to their favorable prognosis. More aggressive ALCLs might be pharmacologically reprogrammed to a DUSP22-like immunogenic molecular signature through the use of demethylating agents and/or immune checkpoint inhibitors.",
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T1 - Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements

AU - Luchtel, Rebecca

AU - Dasari, Surendra

AU - Oishi, Naoki

AU - Pedersen, Martin Bjerregård

AU - Hu, Guangzhen

AU - Rech, Karen L.

AU - Ketterling, Rhett P.

AU - Sidhu, Jagmohan

AU - Wang, Xueju

AU - Katoh, Ryohei

AU - Dogan, Ahmet

AU - Kip, N. Sertac

AU - Cunningham, Julie M

AU - Sun, Zhifu

AU - Baheti, Saurabh

AU - Porcher, Julie C.

AU - Said, Jonathan W.

AU - Jiang, Liuyan

AU - Hamilton-Dutoit, Stephen Jacques

AU - Møller, Michael Boe

AU - Nørgaard, Peter

AU - Bennani, Nabila

AU - Chng, Wee Joo

AU - Huang, Gaofeng

AU - Link, Brian K.

AU - Facchetti, Fabio

AU - Cerhan, James R

AU - D’Amore, Francesco

AU - Ansell, Stephen Maxted

AU - Feldman, Andrew L

PY - 2018/9/27

Y1 - 2018/9/27

N2 - Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell non-Hodgkin lymphomas broadly segregated into ALK-positive and ALK-negative types. Although ALK-positive ALCLs consistently bear rearrangements of the ALK tyrosine kinase gene, ALK-negative ALCLs are clinically and genetically heterogeneous. About 30% of ALK-negative ALCLs have rearrangements of DUSP22 and have excellent long-term outcomes with standard therapy. To better understand this group of tumors, we evaluated their molecular signature using gene expression profiling. DUSP22-rearranged ALCLs belonged to a distinct subset of ALCLs that lacked expression of genes associated with JAK-STAT3 signaling, a pathway contributing to growth in the majority of ALCLs. Reverse-phase protein array and immunohistochemical studies confirmed the lack of activated STAT3 in DUSP22-rearranged ALCLs. DUSP22-rearranged ALCLs also overexpressed immunogenic cancer-testis antigen (CTA) genes and showed marked DNA hypomethylation by reduced representation bi-sulfate sequencing and DNA methylation arrays. Pharmacologic DNA demethylation in ALCL cells recapitulated the overexpression of CTAs and other DUSP22 signature genes. In addition, DUSP22-rear-ranged ALCLs minimally expressed PD-L1 compared with other ALCLs, but showed high expression of the costimulatory gene CD58 and HLA class II. Taken together, these findings indicate that DUSP22 rearrangements define a molecularly distinct subgroup of ALCLs, and that immunogenic cues related to antigenicity, costimulatory molecule expression, and inactivity of the PD-1/PD-L1 immune checkpoint likely contribute to their favorable prognosis. More aggressive ALCLs might be pharmacologically reprogrammed to a DUSP22-like immunogenic molecular signature through the use of demethylating agents and/or immune checkpoint inhibitors.

AB - Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell non-Hodgkin lymphomas broadly segregated into ALK-positive and ALK-negative types. Although ALK-positive ALCLs consistently bear rearrangements of the ALK tyrosine kinase gene, ALK-negative ALCLs are clinically and genetically heterogeneous. About 30% of ALK-negative ALCLs have rearrangements of DUSP22 and have excellent long-term outcomes with standard therapy. To better understand this group of tumors, we evaluated their molecular signature using gene expression profiling. DUSP22-rearranged ALCLs belonged to a distinct subset of ALCLs that lacked expression of genes associated with JAK-STAT3 signaling, a pathway contributing to growth in the majority of ALCLs. Reverse-phase protein array and immunohistochemical studies confirmed the lack of activated STAT3 in DUSP22-rearranged ALCLs. DUSP22-rearranged ALCLs also overexpressed immunogenic cancer-testis antigen (CTA) genes and showed marked DNA hypomethylation by reduced representation bi-sulfate sequencing and DNA methylation arrays. Pharmacologic DNA demethylation in ALCL cells recapitulated the overexpression of CTAs and other DUSP22 signature genes. In addition, DUSP22-rear-ranged ALCLs minimally expressed PD-L1 compared with other ALCLs, but showed high expression of the costimulatory gene CD58 and HLA class II. Taken together, these findings indicate that DUSP22 rearrangements define a molecularly distinct subgroup of ALCLs, and that immunogenic cues related to antigenicity, costimulatory molecule expression, and inactivity of the PD-1/PD-L1 immune checkpoint likely contribute to their favorable prognosis. More aggressive ALCLs might be pharmacologically reprogrammed to a DUSP22-like immunogenic molecular signature through the use of demethylating agents and/or immune checkpoint inhibitors.

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