RESUMEN
The spectrum of cutaneous CD30-positive lymphoproliferative disorders (LPDs) includes lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Chromosomal translocations targeting tyrosine kinases in CD30-positive LPDs have not been described. Using whole-transcriptome sequencing, we identified a chimeric fusion involving NPM1 (5q35) and TYK2 (19p13) that encodes an NPM1-TYK2 protein containing the oligomerization domain of NPM1 and an intact catalytic domain in TYK2. Fluorescence in situ hybridization revealed NPM1-TYK2 fusions in 2 of 47 (4%) primary cases of CD30-positive LPDs and was absent in other mature T-cell neoplasms (n = 151). Functionally, NPM1-TYK2 induced constitutive TYK2, signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activation. Conversely, a kinase-defective NPM1-TYK2 mutant abrogated STAT1/3/5 signaling. Finally, short hairpin RNA-mediated silencing of TYK2 abrogated lymphoma cell growth. This is the first report of recurrent translocations involving TYK2, and it highlights the novel therapeutic opportunities in the treatment of CD30-positive LPDs with TYK2 translocations.
Asunto(s)
Antígeno Ki-1/genética , Linfoma Anaplásico Cutáneo Primario de Células Grandes/genética , Papulosis Linfomatoide/genética , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Neoplasias Cutáneas/genética , TYK2 Quinasa/genética , Western Blotting , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Hibridación Fluorescente in Situ , Antígeno Ki-1/metabolismo , Linfoma Anaplásico Cutáneo Primario de Células Grandes/metabolismo , Linfoma Anaplásico Cutáneo Primario de Células Grandes/patología , Papulosis Linfomatoide/metabolismo , Papulosis Linfomatoide/patología , Mutación , Proteínas Nucleares/metabolismo , Nucleofosmina , Fusión de Oncogenes , Proteínas de Fusión Oncogénica/metabolismo , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/metabolismo , Transducción de Señal/genética , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , TYK2 Quinasa/metabolismo , Transcriptoma/genéticaRESUMEN
The promyelocytic leukemia zinc-finger (PLZF) is essential for the development of innate T cells (as represented by natural killer T cells) for acquisition of their unique innate immune properties. We evaluated the PLZF protein expression in a variety of immature and mature lymphoid malignancies. PLZF was preferentially expressed in T-lymphoblastic lymphoma/acute lymphoblastic leukemia (T-LBL/ALL) in 50% of the 54 cases. Among 51 cases of peripheral T-cell lymphoma not otherwise specified, only one (2%) expressed PLZF. One mycosis fungoides case expressed PLZF in lymph node involved by tumor. Otherwise, PLZF was not detected in any other type of lymphoma. In T-LBL/ALL, PLZF expression was more common in CD4/CD8 double-negative (67%) or CD8 single-positive subtypes (73%) than in CD4/CD8 double-positive (13%) and CD4 single-positive subtypes (0%) (P=0.001). Importantly, PLZF and CD1a expression were mutually exclusive in T-LBL/ALL (P=0.001). This was also the case for T-cell receptor ßF1 expression (P=0.000). Most (96%) of the PLZF-positive T-LBL/ALL cases showed initial bone marrow involvement compared with 39% of PLZF-negative cases (P=0.000). Based on these findings, we suggest that T-LBL/ALLs that express PLZF arise from early immature double-negative thymocytes when the T-cell receptor ß chain has not yet expressed or innate T-cell precursors, and strongly imply bone marrow involvement.