Clonal diversity is a consequence of cancer cell evolution driven by Darwinian selection. Precise characterization of clonal architecture is essential to understand the evolutionary history of tumor development and its association with treatment resistance. Here, using a single-cell DNA sequencing, we report the clonal architecture and mutational histories of 123 acute myeloid leukemia (AML) patients. The single-cell data reveals cell-level mutation co-occurrence and enables reconstruction of mutational histories characterized by linear and branching patterns of clonal evolution, with the latter including convergent evolution. Through xenotransplantion, we show leukemia initiating capabilities of individual subclones evolving in parallel. Also, by simultaneous single-cell DNA and cell surface protein analysis, we illustrate both genetic and phenotypic evolution in AML. Lastly, single-cell analysis of longitudinal samples reveals underlying evolutionary process of therapeutic resistance. Together, these data unravel clonal diversity and evolution patterns of AML, and highlight their clinical relevance in the era of precision medicine.

Key Points• PD-L1 expression in neoplastic cells or stromal cells is associated with poor or good prognosis in ATLL, respectively.• Distinction of expression pattern of PD-L1 might be important on the point of prognostic and therapeutic markers in ATLL. The expression of nPD-L1 and miPD-L1 maintained prognostic value for OS in multivariate analysis (P 5 .0322 and P 5 .0014, respectively). This is the first report describing the clinicopathological features and outcomes of PD-L1 expression in ATLL. More detailed studies will disclose clinical and biological significance of PD-L1 expression in ATLL. (Blood. 2016;128(10):1374-1381

Methotrexate (MTX) carries a risk of lymphoproliferative disorders (LPDs), but MTX-associated LPDs (MTX-LPDs) can resolve spontaneously after MTX withdrawal. However, the precise clinicopathologic features of MTX-LPD remain unclear. We aimed to investigate the clinicopathologic characteristics, outcomes, and prognostic factors for histologic types of MTX-LPD. Paraffin-embedded tissue samples of 219 patients with MTX-LPD were analyzed. In total, 30,33,106, and 26 had reactive lymphoid hyperplasia (RH), polymorphic-LPD (Poly-LPD), diffuse large B-cell lymphomas (DLBCLs), and classic Hodgkin lymphoma (CHL), respectively. The clinicopathologic features of RH, Poly-LPD, DLBCLs, and CHL were as follows: extranodal involvement: 13.8% (4/29), 36.4% (12/33), 69.5% (73/105), and 15.4% (4/26); Epstein-Barr virus encoded RNA positivity: 55.2% (16/29), 71.9% (23/32), 45.3% (48/106), and 76.9% (20/26); necrosis: 0% (0/29), 51.5% (17/33), 34.3% (36/105), and 12.0% (3/25); and Hodgkin Reed-Sternberg-like cells: 17.2% (5/29), 50% (14/28), and 19.8% (21/106). The median duration from MTX withdrawal to the time of disease regression was 10.4, 3.0, 4.2, and 2.7 months for RH, Poly-LPD, DLBCLs, and CHL. After MTX withdrawal, progression-free survival was the greatest for RH, followed by for Poly-LPD, DLBCL, and CHL (all P<0.05). Overall survival did not differ significantly between the groups. On univariate analysis, the predictive factors for progression-free survival included plasma cell infiltrate for CHL, eosinophil infiltrate, age above 70 years, and extensive necrosis for Poly-LPD, while they were Epstein-Barr virus encoded RNA positivity and International Prognostic Index risk for DLBCL on multivariate analysis. In conclusion, histologic categorization and histology-specific factors could be useful for predicting MTX-LPD progression after MTX withdrawal.

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The characteristics of adult patients with chronic active Epstein-Barr virus infection are poorly recognized, hindering early diagnosis and an improved prognosis. We studied 54 patients with adult-onset chronic active Epstein-Barr virus infection diagnosed between 2005 and 2015. Adult onset was defined as an estimated age of onset of 15 years or older. To characterize the clinical features of these adults, we compared them to those of 75 pediatric cases (estimated age of onset <15 years). We compared the prognosis of adult-onset chronic active Epstein-Barr virus infection with that of patients with nasal-type (n=37) and non-nasal-type (n=45) extranodal NK/T-cell lymphoma. The median estimated age of onset of these lymphomas was 39 years (range, 16–86 years). Compared to patients with pediatric-onset disease, those in whom the chronic active Epstein-Barr virus infection developed in adulthood had a significantly decreased incidence of fever (P=0.005), but greater frequency of skin lesions (P<0.001). Moreover, hypersensitivity to mosquito bites and the occurrence of hydroa vacciniforme were less frequent in patients with adult-onset disease (P<0.001 and P=0.0238, respectively). Thrombocytopenia, high Epstein-Barr virus nuclear antigen antibody titer, and the presence of hemophagocytic syndrome were associated with a poor prognosis (P=0.0087, P=0.0236, and P=0.0149, respectively). Allogeneic hematopoietic stem cell transplantation may improve survival (P=0.0289). Compared to pediatric-onset chronic active Epstein-Barr virus infection and extranodal NK/T-cell lymphoma, adult-onset chronic active Epstein-Barr virus infection had a poorer prognosis (P<0.001 and P=0.0484, respectively). Chronic active Epstein-Barr virus infection can develop in a wide age range, with clinical differences between adult-onset and pediatric-onset disease. Adult-onset chronic active Epstein-Barr virus infection is a disease with a poor prognosis. Further research will be needed.