Gene expression profiling reveals two overarching types of ALCL with distinct targetable biology: an LLMPP study Available to Purchase

• Molecular heterogeneity among ALCLs is largely attributable to two novel gene expression signatures implicating distinct targetable biology.

• An integrated molecular classification of ALCL, applicable to routine practice, stratifies ALCL into clinically relevant subtypes.

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 ALK status, but inadequately addresses molecular heterogeneity and therapeutic vulnerabilities. We studied 689 ALCLs in the Lymphoma/Leukemia Molecular Profiling Project and performed expert consensus review, genetic subtyping (ALK, DUSP22, TP63, and triple-negative), and immunohistochemistry for phospho-STAT3Tyr705. RNAseq with unsupervised gene expression profiling in a sub-cohort (N=393) identified two main molecular types of ALCL that could be predicted with 91% accuracy based on the presence (Type I) or absence (Type II) of phospho-STAT3Y705 expression (P<0.0001). 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 (FDR<0.0001), whereas Type II ALCLs were enriched for non-tyrosine kinase pathways, particularly epigenetic regulators such as EZH2 (FDR<0.0001). EZH2 and H3K27me3 were overexpressed by immunohistochemistry (P<0.0001). Prognosis in systemic ALCL was favorable for DUSP22-rearranged ALCL (5-year OS, 95%; N=49) and ALK+ ALCL (88%; N=101), intermediate for triple-negative ALCL (TN-I, 52% and TN-II, 37%; N=92), and poor for TP63-rearranged ALCL (0%; P<0.0001; N=15). We introduce an integrated molecular classification that preserves currently diagnosed ALCL entities but identifies four 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.