IntroductionMicroRNAs (miRNAs) are small (20-24 nt's), noncoding RNAs that function as key regulators of gene expression. By pairing with the transcripts of protein-coding genes, they mediate cleavage of the targeted mRNAs or repression of their productive translation. [1][2][3] Notably, miRNAs exhibit dynamic temporal and spatial expression patterns, disruption of which may be associated with tumorigenesis. [4][5][6][7] The C13orf25/miR-17-92 cluster encodes 6 miRNAs (miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92). The miR-17-92 cluster is known to be overexpressed in a variety of B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, follicular lymphoma, and mantle cell lymphoma, 5,[8][9][10][11][12][13] all of which arise through various primary and additional genetic changes, including genomic translocations, losses, and amplifications. [8][9][10][11][12][13] Recurrent overexpression of miR-17-92 in B-cell lymphomas suggests the polycistron possesses tumorigenic potential. Consistent with that idea, He et al demonstrated that forced expression of the miR-17-19b-1 (a miR-17-92 variant) in the Eu-myc transgenic mouse model of B-cell lymphoma accelerated disease onset and progression. 5 This suggests dysregulation of the miR-17-92 polycistron contributes to lymphomagenesis by repressing tumor suppressor gene(s). The most likely target of miR-17-92 in lymphomagenesis is the proapoptotic protein Bim, 14 which is known to be a tumor suppressor. 15 Recently, Xiao et al generated a mouse line that selectively overexpressed miR-17-92 in their lymphocytes. 16 As a result, these mice developed lymphoproliferative disease and died prematurely. Following activation, B and T cells from these transgenic mice showed increased proliferation and survival as a result of dysregulation of the proapoptotic gene Bcl2l11/Bim. In addition, Ventura et al established a strain of miR-17-92 knockout mice, 17 which enabled the researchers to demonstrate that the miR-17-92 cluster is essential for the survival signal that mediates progression from the pro-B-to the pre-B-cell stage. The absence of miR-17-92 led to elevated Bim protein levels and inhibition of B-cell development. Finally, Koralov et al ablated Dicer in early B-cell progenitors by conditionally deleting dcr-1 in the B-cell lineage of mice. The resulting phenotype was similar to that seen with miR-17-92 deletion, which was characterized by a developmental block at the transition from the pro-B-to the pre-B-cell stage. The researchers also found that cells lacking Dicer showed increased Bim transcription and Bim protein production. 18 All of these reports suggest that down-regulation of Bim mRNA and protein induced by miR-17-92 overexpression could contribute lymphomagenesis via antiapoptotic activity. Nonetheless, Bim is an unlikely target of miR-17-92 in some aggressive B-cell lymphomas, despite overexpression of the polycistron. For instance, Jeko-1 cells, which are derived from an aggressive B-cell lymphoma, exhibit both homozygous...

The gene(s) responsible for natural killer (NK)-cell lymphoma/leukemia have not been identified. In the present study, we found that in NK-cell lymphoma lines (n ‫؍‬ 10) and specimens of primary lymphoma (n ‫؍‬ 10), levels of miR-21 and miR-155 expression were inversely related and were significantly greater than those found in normal natural killer (CD3 ؊ CD56 ؉ ) cells (n ‫؍‬ 8). To determine the functions of these microRNAs in lymphomagenesis, we examined the effects of antisense oligonucleotides (ASOs) tar- IntroductionNatural killer (NK)-cell lymphomas/leukemias are characterized groups of highly aggressive lymphoid malignancies, which are composed of "extranodal NK/T-cell lymphoma, nasal type" and "aggressive NK-cell leukemia." 1 Notably, these 2 subtypes show many similarities in their morphologic features, immunophenotypes, and genotypes and are invariably associated with EpsteinBarr virus (EBV), which suggests they may share the same genetic alterations. To assign a classification, the World Health Organization classification uses cytogenetic and molecular features to characterize lymphoma subtypes. 1 For example, it is known that various genomic translocations and genetic alterations, including BCL2, CCDN1, and c-MYC, occur in B-cell lymphomas. These disease-specific genetic translocations characterize lymphoma subtypes, such as follicular lymphoma characterized by BCL2 rearrangement, mantle-cell lymphoma characterized by CCDN1 rearrangement, and Burkitt lymphoma characterized by c-MYC rearrangement. However, although the World Health Organization classification recognizes NK-cell lymphomas/leukemias as distinct clinicopathologic entities, disease-specific translocations and the gene(s) affected in the 2 subtypes have not yet been identified. It was previously reported that a 6q deletion occurs in approximately 10% to 20% of NK-cell lymphomas/leukemias 2-7 ; however, this loss may not be disease specific because it has been observed in a variety of cancers, including solid tumors and hematologic malignancies. It is currently unclear whether the loss is a primary or progression-associated event.It was recently discovered that some microRNAs (miRNAs) are oncogenic in B-cell lymphomas. For example, aberrant overexpression of 2 miRNAs, miR-17-92 and miR-155, is closely associated with B-cell lymphomagenesis. 8 With respect to miR-17-92, we recently demonstrated that the polycistron can down-regulate CDKN1A/p21 in B-cell lymphomagenesis and promote cell-cycle regulation. 8 Furthermore, it is unlikely that aberrant expression of miRNAs is restricted to B-cell lymphomas, and it may occur in other lymphoma subtypes, including T/NK-cell lymphomas. In the present study, therefore, we used Northern and quantitative polymerase chain reaction (PCR) analyses to screen for and quantitatively assess miRNA expression in NK-cell lymphomas/leukemias and found that miR-21 and miR-155 were overexpressed in NK-cell lymphoma/leukemia. Moreover, the effects of antisense oligonucleotides (ASOs) revealed that miR-21 and miR-15...

MicroRNA (miRNA; miR) is a class of small regulatory RNA molecules, the aberrant expression of which can lead to the development of cancer. We recently reported that overexpression of miR-21 and/or miR-155 leads to activation of the phosphoinositide 3-kinase (PI3K)-AKT pathway in malignant lymphomas expressing CD3 À CD56þ natural killer (NK) cell antigen. Through expression analysis, we show in this study that in both NK/T-cell lymphoma lines and samples of primary lymphoma, levels of miR-150 expression are significantly lower than in normal NK cells. To examine its role in lymphomagenesis, we transduced miR-150 into NK/T-cell lymphoma cells, which increased the incidence of apoptosis and reduced cell proliferation. Moreover, the miR-150 transductants appeared senescent and showed lower telomerase activity, resulting in shortened telomeric DNA. We also found that miR-150 directly downregulated expression of DKC1 and AKT2, reduced levels of phosphorylated AKT ser473/4 and increased levels of tumor suppressors such as Bim and p53. Collectively, these results suggest that miR-150 functions as a tumor suppressor, and that its aberrant downregulation induces continuous activation of the PI3K-AKT pathway, leading to telomerase activation and immortalization of cancer cells. These findings provide new insight into the pathogenesis of malignant lymphoma.

Imatinib mesylate (IM) trough concentration varies among IM-treated chronic myeloid leukemia (CML) patients. Although IM pharmacokinetics is influenced by several enzymes and transporters, little is known about the role of pharmacogenetic variation in IM metabolism. In this study, associations between IM trough concentration, clinical response and 11 single-nucleotide polymorphisms in genes involved in IM pharmacokinetics (ABCB1, ABCC2, ABCG2 CYP3A5, SLC22A1 and SLCO1B3) were investigated among 67 Japanese chronic phase CML patients. IM trough concentration was significantly higher in patients with a major molecular response than in those without one (P¼0.010). No significant correlations between IM trough concentration and age, weight, body mass index or biochemical data were observed. However, the dose-adjusted IM trough concentration was significantly higher in patients with ABCG2 421A than in those with 421C/C (P=0.015). By multivariate regression analysis, only ABCG2 421A was independently predictive of a higher dose-adjusted IM trough concentration (P¼0.015). Moreover, previous studies have shown that the ABCG2 421C4A (p.Q141K) variant is prevalent among Japanese and Han Chinese individuals and less common among Africans and Caucasians. Together, these data indicate that plasma IM concentration monitoring and prospective ABCG2 421C4A genotyping may improve the efficacy of IM therapy, particularly among Asian CML patients.

The purpose of this trial was to evaluate the efficacy of 2-year consolidation therapy with nilotinib, at a dose of 300 mg twice daily, for achieving treatment-free remission in chronic myeloid leukemia patients with a deep molecular response (BCR-ABL1IS ≤0.0032%). Successful treatment-free remission was defined as no confirmed loss of deep molecular response. We recruited 96 Japanese patients, of whom 78 sustained a deep molecular response during the consolidation phase and were therefore eligible to discontinue nilotinib in the treatment-free remission phase; of these, 53 patients (67.9%; 95% confidence interval: 56.4–78.1%) remained free from molecular recurrence in the first 12 months. The estimated 3-year treatment-free survival was 62.8%. Nilotinib was readministered to all patients (n=29) who experienced a molecular recurrence during the treatment-free remission phase. After restarting treatment, rapid deep molecular response returned in 25 patients (86.2%), with 50% of patients achieving a deep molecular response within 3.5 months. Tyrosine kinase inhibitor withdrawal syndrome was reported in 11/78 patients during the early treatment-free remission phase. The treatment-free survival curve was significantly better in patients with undetectable molecular residual disease than in patients without (3-year treatment-free survival, 75.6 versus 48.6%, respectively; P=0.0126 by the log-rank test). There were no significant differences in treatment-free survival between subgroups based on tyrosine kinase inhibitor treatment before the nilotinib consolidation phase, tyrosine kinase inhibitor-withdrawal syndrome, or absolute number of natural killer cells. The results of this study indicate that it is safe and feasible to stop tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia who have achieved a sustained deep molecular response with 2 years of treatment with nilotinib. This study was registered with UMIN-CTR (UMIN000005904).