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High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd-MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled. Patients who achieved complete remission (CR) were randomly assigned to receive therapy containing Hd-MTX (3 g/m2 ) or Id-MTX (0.5 g/m2 ). A total of 360 patients were enrolled. The CR rate was 86%. A total of 115 and 114 patients were assigned to the Hd-MTX and Id-MTX groups, respectively. The estimated 5-year disease-free survival rate of the Hd-MTX group was 58%, which was significantly better than that of the Id-MTX group at 32% (P=0.0218). The frequencies of severe adverse events were not significantly different. We herein demonstrated the effectiveness and safety of Hd-MTX therapy for adult Ph-negative ALL. Our results provide a strong rationale for protocols containing Hd-MTX therapy being applied to the treatment of adult ALL.

To identify oncogenes in leukemias, we performed large-scale resequencing of the leukemia genome using DNA sequence arrays that determine ∼9 Mbp of sequence corresponding to the exons or exon–intron boundaries of 5648 protein-coding genes. Hybridization of genomic DNA from CD34-positive blasts of acute myeloid leukemia ( n =19) or myeloproliferative disorder ( n =1) with the arrays identified 9148 nonsynonymous nucleotide changes. Subsequent analysis showed that most of these changes were also present in the genomic DNA of the paired controls, with 11 somatic changes identified only in the leukemic blasts. One of these latter changes results in a Met-to-Ile substitution at amino-acid position 511 of Janus kinase 3 (JAK3), and the JAK3(M511I) protein exhibited transforming potential both in vitro and in vivo . Further screening for JAK3 mutations showed novel and known transforming changes in a total of 9 out of 286 cases of leukemia. Our experiments also showed a somatic change responsible for an Arg-to-His substitution at amino-acid position 882 of DNA methyltransferase 3A, which resulted in a loss of DNA methylation activity of >50%. Our data have thus shown a unique profile of gene mutations in human leukemia.

To clarify the cooperative roles of recurrently identified mutations and to establish a more precise risk classification system in acute myeloid leukemia (AML), we comprehensively analyzed mutations in 51 genes, as well as cytogenetics and 11 chimeric transcripts, in 197 adult patients with de novo AML who were registered in the Japan Adult Leukemia Study Group AML201 study. We identified a total of 505 mutations in 44 genes, while only five genes, FLT3, NPM1, CEBPA, DNMT3A and KIT , were mutated in more than 10% of the patients. Although several cooperative and exclusive mutation patterns were observed, the accumulated mutation number was higher in cytogenetically normal AML and lower in AML with RUNX1-RUNX1T1 and CBFB-MYH11 , indicating a strong potential of these translocations for the initiation of AML. Furthermore, we evaluated the prognostic impacts of each sole mutation and the combinations of mutations and/or cytogenetics, and demonstrated that AML patients could be clearly stratified into five risk groups for overall survival by including the mutation status of DNMT3A , MLL -PTD and TP53 genes in the risk classification system of the European LeukemiaNet. These results indicate that the prognosis of AML could be stratified by the major mutation status in combination with cytogenetics.

Two distinct forms of fms-like tyrosine kinase (FLT3) gene aberrations, internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations, have been recognized in a substantial proportion of patients with acute myeloid leukemia (AML). To investigate their prognostic significance, we performed a meta-analysis of the four published studies that provided survival information according to the FLT3 status: ITD, TKD mutation, and wild type. The summary hazard ratios for disease-free survival (DFS) were 1.88 (95% confidence interval (CI) 1.58-2.23; P<0.001) for FLT3 mutations, 1.86 (95% CI: 1.52-2.29; P<0.001) for ITD, and 1.90 (95% CI: 1.40-2.60; P<0.001) for TKD mutation. The corresponding ratios for overall survival were 1.61 (95% CI: 1.37-1.89; P<0.001), 1.68 (95% CI: 1.39-2.03; P<0.001), and 1.37 (95% CI: 0.94-2.01; P=0.104). Neither white blood cell count at diagnosis nor cytogenetic risk category was a significant source of heterogeneity. These findings indicate that FLT3 mutations have an adverse effect on the outcome for AML, and that the negative impact of TKD mutation seems comparable to that of ITD with regard to DFS. Although it should be borne in mind that this meta-analysis was based on data abstracted from observational studies, these results may justify the risk-adapted therapeutic strategies for AML according to the FLT3 status.

Intravascular large B-cell lymphoma (IVLBCL) is a distinct disease entity with the peculiar characteristic that tumor cells proliferate within vessels. Despite recent advances in understanding the disease from clinical aspects, the underlying pathogenesis remains unknown. Here we demonstrate analyses of IVLBCL biology using four xenograft mouse models established from primary IVLBCL samples. In all four models, the main characteristic of IVLBCL tumor cell proliferation within vessels was retained. Time-lapse engraftment analyses revealed that the tumor cells initially engrafted and proliferated in the sinusoids and vessels in the liver and then engrafted and proliferated in multiple organs. Intriguingly, serial passage of tumor cells from the adrenal gland of a transplanted mouse developed from primary patient bone marrow cells into a second mouse showed that the tumor cells mainly distributed into the adrenal gland in the second mouse, implying the existence of clonal selection and/or evolution at engraftment of a specific organ. Gene expression profiling analyses demonstrated that the gene set associated with cell migration was enriched for normal peripheral blood B cells, indicating that inhibition of cell migration might be involved in IVLBCL pathogenesis. In conclusion, the mouse xenograft models described here are essential tools for uncovering IVLBCL biology.

Although tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML), the ability of TKIs to eradicate CML remains uncertain and patients must continue TKI therapy for indefinite periods. In this study, we performed whole-exome sequencing to identify somatic mutations in 24 patients with newly diagnosed chronic phase CML who were registered in the JALSG CML212 study. We identified 191 somatic mutations other than the BCR-ABL1 fusion gene (median 8, range 1–17). Age, hemoglobin concentration and white blood cell counts were correlated with the number of mutations. Patients with mutations ⩾6 showed higher rate of achieving major molecular response than those<6 ( P =0.0381). Mutations in epigenetic regulator, ASXL1 , TET2 , TET3 , KDM1A and MSH6 were found in 25% of patients. TET2 or TET3 , AKT1 and RUNX1 were mutated in one patient each. ASXL1 was mutated within exon 12 in three cases. Mutated genes were significantly enriched with cell signaling and cell division pathways. Furthermore, DNA copy number analysis showed that 2 of 24 patients had uniparental disomy of chromosome 1p or 3q, which disappeared major molecular response was achieved. These mutations may play significant roles in CML pathogenesis in addition to the strong driver mutation BCR-ABL1 .