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Angioimmunoblastic T-cell lymphoma (AITL) is proposed to be initiated by age-related clonal hematopoiesis (ACH) with TET2 mutations, whereas the G17V RHOA mutation in immature cells with TET2 mutations promotes development of T follicular helper-like tumor cells. Here, we investigated the mechanism by which TET2-mutant immune cells enable AITL development, using mouse models and human samples. Among the two mouse models, mice lacking Tet2 in all the blood cells (Mx-Cre × Tet2flox/flox× G17V RHOA transgenic mice) spontaneously developed AITL for approximately up to a year, while mice lacking Tet2 only in the T cells (Cd4-Cre × Tet2flox/flox× G17V RHOA transgenic mice) did not. Therefore, Tet2-deficient immune cells function as a niche for AITL development. Single-cell RNA-sequencing (scRNA-seq) of > 50,000 cells from mouse and human AITL samples revealed significant expansion of aberrant B cells (exhibiting properties of activating light zone‒like and proliferative dark zone‒like germinal center B (GCB) cells). The GCB cells in AITL clonally evolved with recurrent mutations in genes related to core histones. In silico network analysis using scRNA-seq data identified Cd40-Cd40lg as a possible mediator of GCB and tumor cell cluster interactions. Treatment of AITL model mice with anti-Cd40lg inhibitory antibody prolonged survival. The genes expressed in aberrantly expanded GCB cells in murine tumors were also broadly expressed in the B-lineage cells of TET2-mutant human AITL. Therefore, ACH-derived GCB cells could undergo independent clonal evolution and support the tumorigenesis in AITL via the CD40-CD40LG axis.

Summary Other iatrogenic immunodeficiency‐associated lymphoproliferative disorders (OIIA‐LPDs) occur in patients receiving immunosuppressive drugs for autoimmune diseases; however, their clinicopathological and genetic features remain unknown. In the present study, we analysed 67 patients with OIIA‐LPDs, including 36 with diffuse large B‐cell lymphoma (DLBCL)‐type and 19 with Hodgkin lymphoma (HL)‐type. After discontinuation of immunosuppressive drugs, regression without relapse was achieved in 22 of 58 patients. Spontaneous regression was associated with Epstein–Barr virus positivity in DLBCL‐type (P = 0·013). The 2‐year overall survival and progression‐free survival (PFS) at a median follow‐up of 32·4 months were 92·7% and 72·1% respectively. Furthermore, a significant difference in the 2‐year PFS was seen between patients with DLBCL‐type and HL‐type OIIA‐LPDs (81·0% vs. 40·9% respectively, P = 0·021). In targeted sequencing of 47 genes in tumour‐derived DNA from 20 DLBCL‐type OIIA‐LPD samples, histone‐lysine N‐methyltransferase 2D (KMT2D; eight, 40%) and tumour necrosis factor receptor superfamily member 14 (TNFRSF14; six, 30%) were the most frequently mutated genes. TNF alpha‐induced protein 3 (TNFAIP3) mutations were present in four patients (20%) with DLBCL‐type OIIA‐LPD. Cases with DLBCL‐type OIIA‐LPD harbouring TNFAIP3 mutations had shorter PFS and required early initiation of first chemotherapy. There were no significant factors for spontaneous regression or response rates according to the presence of mutations. Overall, OIIA‐LPDs, especially DLBCL‐types, showed favourable prognoses.

We report the case of a 76-year-old man who was diagnosed as having chronic myeloid leukemia (CML) with p190 BCR-ABL while receiving treatment for symptomatic multiple myeloma (MM). The diagnosis of MM was based on the presence of serum M-protein, abnormal plasma cells in the bone marrow, and lytic bone lesions. The patient achieved a partial response to lenalidomide and dexamethasone treatment. However, 2 years after the diagnosis of MM, the patient developed leukocytosis with granulocytosis, anemia, and thrombocytopenia. Bone marrow examination revealed Philadelphia chromosomes and chimeric p190 BCR-ABL mRNA. Fluorescence in situ hybridization also revealed BCR-ABL-positive neutrophils in the peripheral blood, which suggested the emergence of CML with p190 BCR-ABL. The codevelopment of MM and CML is very rare, and this is the first report describing p190 BCR-ABL-type CML coexisting with MM. Moreover, we have reviewed the literature regarding the coexistence of these diseases.

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