BACKGROUND. T-cell non-Hodgkin lymphomas (T-NHL) are more aggressive and patients have a poorer prognosis compared with patients with the corresponding B-cell lymphomas. Although intensive treatments have been developed, it is unknown whether they are more effective than CHOP chemotherapy (cyclophosphamide, doxorubicin, oncovorin, and prednisone).METHODS. The authors' retrospective study evaluated the clinical outcome of 135 previously untreated patients with T-NHL who were treated at The University of Texas M. D. Anderson Cancer Center (Houston, TX) between 1996 and 2002. Lymphomas with T-cell histologies with the exception of mycosis fungoides were included. RESULTS.The estimated median overall survival was 46 months. Thirty-seven percent of the patients received CHOP therapy, 48% received intensive therapy, and 15% received other therapy. The estimated 3-year overall survival rates were 62% for the patients treated with CHOP therapy and 56% for the patients who received intensive therapy. After the exclusion of patients with anaplastic large cell lymphoma (ALCL), who are known to have a better prognosis than patients with other T-NHLs, the estimated 3-year overall survival rates were 43% for the patients treated with CHOP therapy and 49% for the patients who received intensive therapy. Parameters that may be independent prognostic factors for survival in T-NHL, excluding ALCL, included ECOG performance status Ն 2, beta-2-microglobulin level Ͼ 2 mg/L, lactate dehydrogenase level higher than normal, bulky disease Ն 7 cm, and a higher international prognostic index and tumor score. CONCLUSIONS.The current study data suggested that patients treated with intensive therapies did not fare better than those treated with CHOP therapy. New treatment regimens need to be developed for patients with T-NHL.

DNMT3A is frequently mutated in acute myeloid leukemia (AML). To explore the features of human AML with the hotspot DNMT3A R882H mutation, we generated Dnmt3a R878H conditional knockin mice, which developed AML with enlarged Lin − Sca1 + cKit + cell compartments. The transcriptome and DNA methylation profiling of bulk leukemic cells and the single-cell RNA sequencing of leukemic stem/progenitor cells revealed significant changes in gene expression and epigenetic regulatory patterns that cause differentiation arrest and growth advantage. Consistent with leukemic cell accumulation in G 2 /M phase, CDK1 was up-regulated due to mTOR activation associated with DNA hypomethylation. Overexpressed CDK1-mediated EZH2 phosphorylation resulted in an abnormal trimethylation of H3K27 profile. The mTOR inhibitor rapamycin elicited a significant therapeutic response in Dnmt3a R878H/WT mice.have been identified in a subset of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphoblastic leukemia (ALL), with DNMT3A R882 being the hotspot (1-4). Clinical features of most AML cases with DNMT3A mutations include preferential involvement of a monocytic lineage (AML-M4 and -M5 subtypes), thrombocytosis, onset at a relatively old age, and poor prognosis (2, 5, 6). Careful genotypephenotype correlations suggest that patients manifest DNMT3A mutations in preleukemic hematopoietic stem cells (HSCs)/multipotent progenitors (MPPs), which exhibit a competitive advantage over normal HSCs. Because these mutations occur at a very early stage among genetic abnormalities, they are likely involved in the development of leukemia (7,8).Functionally, the DNMT3A R882 mutation might disrupt epigenetic regulation. This kind of DNMT3A mutation confers reduced methyltransferase activity and promotes the possibility of dominant-negative consequences compared with the wild-type (WT) allele (2, 9, 10). Moreover, the DNMT3A mutation causes aberrant DNA hypomethylation and up-regulates a series of target genes involved in AML pathogenesis (11-13).In vivo animal tests have shown that the Dnmt3a gene plays an essential role in hematopoiesis regulation. Dnmt3a −/− HSCs expand remarkably, but their differentiation is inhibited when Dnmt3a is conditionally inactivated in the murine hematopoietic system; this phenomenon is consistent with a preleukemic state (7). Moreover, all lethally irradiated mice transplanted with Dnmt3a-deleted HSCs died within 1 y and were diagnosed with a spectrum of malignancies similar to those observed in patients carrying DNMT3A mutations, including MDS, AML, primary myelofibrosis, and ALL, suggesting that Dnmt3a functions as a tumor suppressor (7). With a second hit of mutations in various genes such as N-RAS, C-KIT, or FLT3 in Dnmt3a −/− mice, Dnmt3a deletion induces leukemic transformation (14, 15). Although these results indicate a major role of Dnmt3a deletion in facilitating the development of leukemia, the in vivo roles of DNMT3A mutants in leukemogenesis still need to be addressed. In our previous work, b...

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Immunosuppression is an important factor for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Follicular helper T cells (Tfh cells) play an anti-tumor role in various malignant solid tumors and predict better patient prognosis. In the present study, we aimed to determine the immunosuppressive mechanism associated with Tfh cells and explore a new strategy to improve the tumor microenvironment of PDAC. Flow cytometry was used to detect the infiltration and proportion of Tfh cells in tumor tissues and peripheral blood from patients with PDAC. The spatial correlations of Tfh cells with related immune cells were evaluated using immunofluorescence. The function of Tfh cells was examined using in vitro and in vivo model systems. The high infiltration of Tfh cells predicted better prognosis in patients with PDAC. Tfh cells recruited CD8+ T cells and B cells by secreting C-X-C motif chemokine ligand 13 (CXCL13), and promoted the maturation of B cells into antibody-producing plasma cells by secreting interleukin 21 (IL-21), thereby promoting the formation of an immunoactive tumor microenvironment. The function of Tfh cells was inhibited by the programmed cell death 1 ligand 1 (PD-L1)/programmed cell death 1 (PD-1) signaling pathway in PDAC, which could be reversed using neoadjuvant chemotherapy. Treatment with recombinant CXCL13, IL-21 and Tfh cells alleviated tumor growth and enhanced the infiltration of CD8+ T cells and B cells, as well as B cell maturation in a PDAC mouse model. Our results revealed the important role of Tfh cells in mediating anti-tumor cellular immunity and humoral immunity in PDAC via secreting CXCL13 and IL-21 and determined a novel mechanism of immunosuppression in PDAC.