Gene expression profiling reveals 2 overarching types of ALCL with distinct targetable biology: an LLMPP study

Anaplastic large cell lymphomas (ALCLs) are CD30+ T-cell lymphomas that share pathologic features but differ in presentation, outcome, and genetics. Current classification incorporates clinical presentation and anaplastic lymphoma kinase (ALK) status but inadequately addresses molecular heterogeneity and therapeutic vulnerabilities. We studied 689 patients with ALCL in the LLMPP (Lymphoma/Leukemia Molecular Profiling Project) and performed expert consensus review, genetic subtyping (ALK, DUSP22, TP63, and triple negative), and immunohistochemistry for phosphorylated STAT3Tyr705. RNA sequencing with unsupervised gene expression profiling in 393 patients identified 2 main molecular types of ALCL that could be predicted with 91% accuracy based on the presence (type I) or absence (type II) of phosphorylated STAT3Y705 expression. Type I ALCLs included ALK+ ALCL and a subset of triple-negative ALCLs (TN-I); type II ALCLs included tumors with DUSP22 and/or TP63 rearrangements and the remaining triple-negative ALCLs (TN-II). Type I ALCLs were enriched for JAK-STAT3, whereas type II ALCLs were enriched for non-tyrosine kinase pathways, particularly epigenetic regulators such as EZH2. Immunohistochemistry showed overexpression of EZH2 and its trimethylated substrate H3K27. Prognosis in systemic ALCL was favorable for DUSP22-rearranged ALCL (5-year overall survival, 95%) and ALK+ ALCL (88%), intermediate for triple-negative ALCL (TN-I, 52% and TN-II, 37%), and poor for TP63-rearranged ALCL (0%). We introduce an integrated molecular classification that preserves currently diagnosed ALCL entities but identifies 4 molecularly distinct ALK- ALCL subtypes (DUSP22-rearranged, TP63-rearranged, TN-I, and TN-II). This classification can be easily implemented on paraffin tissue in routine practice or clinical trials, and stratifies ALCL into diagnostically, prognostically, biologically, and potentially therapeutically relevant subtypes.

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Journal
Blood
Published
2025-12-02
DOI
https://doi.org/10.1182/blood.2024027700
Citations
1
Primary Topic
Lymphoma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
1.47
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article

Gene expression profiling reveals 2 overarching types of ALCL with distinct targetable biology: an LLMPP study

L. Jeffrey Medeiros, Kai Fu, Stefania Pittaluga, Yu Zeng et al.
1 citations
Blood
Lymphoma Diagnosis and Treatment
1.47
article

Gene expression profiling reveals 2 overarching types of ALCL with distinct targetable biology: an LLMPP study

L. Jeffrey Medeiros, Kai Fu, Stefania Pittaluga, Yu Zeng, Giorgio Inghirami, Pedro Farinha, Ahmed Abdulrahman, Weina Chen, Laura K. Hilton, Lisa M. Rimsza, Kerry J. Savage, Ryan A. Wilcox, David W. Scott, Alejandro Ariel Gru, Anamarija M. Perry, Andreas Rosenwald, Joo Y. Song, Elı́as Campo, Min Shi, Philipp W. Raess, Young Hyeh Ko, Timothy C. Greiner, Sarah Lynn Ondrejka, Liuyan Jiang, Javeed Iqbal, Eric Mou, Graham W. Slack, Akira Satou, Matthew J. Maurer, Roberto N. Miranda, Stephen M. Ansell, James R. Cook, Susan L. Slager, Brad S. Kahl, David L. Jaye, Laurence de Leval, Catalina Amador, James R. Cerhan, Kennosuke Karube, Naoki Oishi, Ryan D. Morin, Jan Delabie, Jennifer Rose Chapman, Xiaojun Wu, Elaine S. Jaffe, Andrew L. Feldman, Hao‐Wei Wang, Wing C. Chan, Carlos Barrionuevo, Xueju Wang, George Wright, Tadashi Yoshino, G. Ott, Guangzhen Hu, Surendra Dasari
article en
1 citations

Abstract

Anaplastic large cell lymphomas (ALCLs) are CD30+ T-cell lymphomas that share pathologic features but differ in presentation, outcome, and genetics. Current classification incorporates clinical presentation and anaplastic lymphoma kinase (ALK) status but inadequately addresses molecular heterogeneity and therapeutic vulnerabilities. We studied 689 patients with ALCL in the LLMPP (Lymphoma/Leukemia Molecular Profiling Project) and performed expert consensus review, genetic subtyping (ALK, DUSP22, TP63, and triple negative), and immunohistochemistry for phosphorylated STAT3Tyr705. RNA sequencing with unsupervised gene expression profiling in 393 patients identified 2 main molecular types of ALCL that could be predicted with 91% accuracy based on the presence (type I) or absence (type II) of phosphorylated STAT3Y705 expression. Type I ALCLs included ALK+ ALCL and a subset of triple-negative ALCLs (TN-I); type II ALCLs included tumors with DUSP22 and/or TP63 rearrangements and the remaining triple-negative ALCLs (TN-II). Type I ALCLs were enriched for JAK-STAT3, whereas type II ALCLs were enriched for non-tyrosine kinase pathways, particularly epigenetic regulators such as EZH2. Immunohistochemistry showed overexpression of EZH2 and its trimethylated substrate H3K27. Prognosis in systemic ALCL was favorable for DUSP22-rearranged ALCL (5-year overall survival, 95%) and ALK+ ALCL (88%), intermediate for triple-negative ALCL (TN-I, 52% and TN-II, 37%), and poor for TP63-rearranged ALCL (0%). We introduce an integrated molecular classification that preserves currently diagnosed ALCL entities but identifies 4 molecularly distinct ALK- ALCL subtypes (DUSP22-rearranged, TP63-rearranged, TN-I, and TN-II). This classification can be easily implemented on paraffin tissue in routine practice or clinical trials, and stratifies ALCL into diagnostically, prognostically, biologically, and potentially therapeutically relevant subtypes.

BloodVol. 147(11)
Tongji University (CN), University of Iowa (US), BC Cancer Agency (CA), Roswell Park Comprehensive Cancer Center (US), National Institutes of Health (US), City Of Hope National Medical Center (US), Cleveland Clinic (US), Union Hospital (HK), University Health Network (CA), Mayo Clinic (US), The University of Texas MD Anderson Cancer Center (US), University of Arizona (US), Johns Hopkins University (US), University of Miami (US), Emory University (US), Okayama University (JP), Oregon Health & Science University (US), University of Toronto (CA), National University of San Marcos (PE), Jilin University (CN), Washington University in St. Louis (US), Cornell University (US), University of Würzburg (DE), University of Michigan (US), Columbia University Irving Medical Center (US), Johns Hopkins Medicine (US), Korea University Medical Center (KR), Jacksonville College (US), Spinal Cord Injury BC (CA), WinnMed (US), Robert Bosch Hospital (DE), Nagoya University Hospital (JP), Southwestern Medical Center (US), Michigan United (US), Michigan Medicine (US), Michigan Cancer Research Consortium (US), Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (DE), Instituto Nacional de Enfermedades Neoplásicas (PE), Mayo Clinic in Arizona (US), National Cancer Institute (MY), National Cancer Institute (US), Mayo Clinic in Florida (US), Children's Healthcare of Atlanta (US), Johns Hopkins Hospital (US), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Tongji Hospital (CN), Korea University (JP), Union Hospital (CN), Weill Cornell Medicine (US), University of Nebraska Medical Center (US), Nagoya University (JP), University of Yamanashi (JP), The University of Texas Southwestern Medical Center (US), University of Lausanne (CH)
Openalex Percentile: Top 13%
Lymphoma Diagnosis and Treatment
1.47
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