IL-21 is expressed in Hodgkin lymphoma and activates STAT5: evidence that activated STAT5 is required for Hodgkin lymphomagenesis

Classical Hodgkin lymphoma (HL) is a malignant disorder characterized by the presence of neoplastic mononucleated Hodgkin and multinucleated Reed-Sternberg cells. Here, we show that both the interleukin (IL)–21 receptor as well as IL-21 are expressed by HL cells. IL-21 activates signal transducer of activation and transcription 3 (STAT3) and STAT5 in HL cell lines and activated human B cells. Ectopic expression of constitutively active STAT5 in primary human B cells resulted in immortalized B cells that have lost the B-cell phenotype and strongly resembled HL cells, which could partially be rescued by ectopic expression of the B cell–determining transcription factor E47. Data from experiments using reporter assays and overexpression of constitutively active IKK2 support the hypothesis that the STAT5 and nuclear factor-κB (NF-κB) pathways colaborate in HL genesis

Targeted deep sequencing reveals clonal and subclonal mutational signatures in Adult T-cell leukemia/lymphoma and defines an unfavorable indolent subtype

International audienceAdult T-cell leukemia/lymphoma (ATL) carries a poor prognosis even in indolent subtypes. We performed targeted deep sequencing combined with mapping of HTLV-1 proviral integration sites of 61 ATL patients of African and Caribbean origin. This revealed mutations mainly affecting TCR/NF-kB (74%), T-cell trafficking (46%), immune escape (29%), and cell cycle (26%) related pathways, consistent with the genomic landscape previously reported in a large Japanese cohort. To examine the evolution of mutational signatures upon disease progression while tracking the viral integration architecture of the malignant clone, we carried out a longitudinal study of patients who either relapsed or progressed from an indolent to an aggressive subtype. Serial analysis of relapsing patients identified several patterns of clonal evolution. In progressing patients, the longitudinal study revealed NF-kB/NFAT mutations at progression that were present at a subclonal level at diagnosis (allelic frequency < 5%). Moreover, the presence in indolent subtypes of mutations affecting the TCR/NF-kB pathway, whether clonal or subclonal, was associated with significantly shorter time to progression and overall survival. Our observations reveal the clonal dynamics of ATL mutational signatures at relapse and during progression. Our study defines a new subgroup of indolent ATLs characterized by a mutational signature at high risk of transformation