ALK-positive large B-cell lymphomas express a terminal B-cell differentiation program and activated STAT3 but lack MYC rearrangements

• Published in: Modern pathology 2013-10, Vol.26 (10), p.1329-1337
• Main Authors: Valera, Alexandra, Colomo, Lluis, Martínez, Antonio, de Jong, Daphne, Balagué, Olga, Matheu, Gabriel, Martínez, Mónica, Taddesse-Heath, Lekidelu, Jaffe, Elaine S, Bacchi, Carlos E, Campo, Elías
• Format: Article
• Language: English
• Subjects: 631/80/86; 692/420/755; 692/699/67/1990/291/1621/1915; Adult; Anaplastic Lymphoma Kinase; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Cancer; Cell Differentiation - genetics; Female; Genotype & phenotype; Humans; Kinases; Laboratory Medicine; Lymphoma; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Large B-Cell, Diffuse - pathology; Male; Medicine; Medicine & Public Health; original-article; Pathogenesis; Pathology; Phosphorylation; Plasma; Positive Regulatory Domain I-Binding Factor 1; Protein expression; Proteins; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Signal Transduction - genetics; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Tumors
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/modpathol.2013.73

ALK-positive large B-cell lymphoma is an aggressive lymphoid neoplasm characterized by a monomorphic proliferation of immunoblast-like cells expressing a plasmablastic phenotype and carrying ALK rearrangements. MYC rearrangements are frequent in plasmablastic lymphomas, advanced plasma cell myelomas and a subgroup of diffuse large B-cell lymphomas, but their presence in ALK-positive large B-cell lymphomas is unknown. MYC expression is downregulated by BLIMP1, a master modulator of plasma cell differentiation. BLIMP1 and MYC are upregulated by STAT3, a signal transducer activated by ALK. To determine the role of BLIMP1, MYC and STAT3 in the pathogenesis of ALK-positive large B-cell lymphomas, we investigated MYC rearrangement and the expression of MYC, phosphorylated STAT3, BLIMP1, PAX5 and XBP1 in 12 ALK-positive large B-cell lymphomas. All cases expressed ALK with a granular cytoplasmic pattern. Nine cases had a split signal consistent with an ALK rearrangement. Three additional cases showed a deletion of the 5′ or 3′ end of the ALK probe consistent with cryptic translocation. PAX5 was virtually negative in all cases tested, whereas BLIMP1 was expressed in all tumors and XBP1 in 11 of 12. Phosphorylated STAT3 was observed in all cases with a strong and diffuse nuclear pattern. MYC rearrangements were not identified in any tumor, but MYC gains and amplification were detected in six cases and one case, respectively. MYC protein was expressed in all tumors independently of MYC gene alterations. These results indicate that ALK-positive large B-cell lymphomas express a complete plasmablastic differentiation program but, contrary to plasmablastic lymphomas, do not have MYC rearrangements. STAT3 is constantly activated and may be an alternative mechanism to promote MYC expression in these tumors. The relevance of the ALK/STAT3 pathway in the pathogenesis of ALK-positive large B-cell lymphomas may offer an attractive target for new therapies.